System and method for estimating electrical conduction delays from immittance values measured using an implantable medical device

ABSTRACT

Techniques are provided for estimating electrical conduction delays with the heart of a patient based on measured immittance values. In one example, impedance or admittance values are measured within the heart of a patient by a pacemaker or other implantable medical device, then used by the device to estimate cardiac electrical conduction delays. A first set of predetermined conversion factors may be used to convert the measured immittance values into conduction delay values. In some examples, the device then uses the estimated conduction delay values to estimate LAP or other cardiac pressure values. A second set of predetermined conversion factors may be used to convert the estimated conduction delays into pressure values. Techniques are also described for adaptively adjusting pacing parameters based on estimated LAP.

PRIORITY CLAIM

This application is a Divisional application of and claims priority andother benefits from U.S. patent application Ser. No. 12/127,963(Attorney Docket No. A08P3008), filed May 28, 2008, entitled “SYSTEM ANDMETHOD FOR ESTIMATING ELECTRICAL CONDUCTION DELAYS FROM IMMITTANCEVALUES MEASURED USING AN IMPLANTABLE MEDICAL DEVICE”, incorporatedherein by reference in its entirety.

RELATED APPLICATIONS

This application claims priority on U.S. patent application Ser. No.11/779,350, of Wenzel et al., filed Jul. 18, 2007, entitled, “System andMethod for Estimating Cardiac Pressure based on Cardiac ElectricalConduction Delays using an Implantable Medical Device,” (Attorney DocketNo. A07P3015-US1), which claimed priority on U.S. Provisional PatentApplication No. 60/910,060 of Wenzel et al., entitled, “System andMethod for Estimating Left Atrial Pressure based on Intra-CardiacConduction Time Delays,” filed Apr. 4, 2007, which are both fullyincorporated by reference herein. This application is also related toU.S. patent application Ser. No. 11/779,350, of Wenzel et al., entitled,“System and Method for Estimating Cardiac Pressure based on CardiacElectrical Conduction Delays using an Implantable Medical Device,” filedJul. 18, 2007, (Attorney Docket No. A07P3015-US2).

FIELD OF THE INVENTION

The invention relates generally to implantable medical devices such aspacemakers and implantable cardioverter defibrillators (ICDs) and inparticular to techniques for estimating conduction delays and cardiacpressure values (particularly left atrial pressure (LAP)) for use indetecting and evaluating heart failure and related conditions and toautomatically adjust pacing parameters or the like.

BACKGROUND OF THE INVENTION

Heart failure is a debilitating disease in which abnormal function ofthe heart leads to inadequate blood flow to fulfill the needs of thetissues and organs of the body. Typically, the heart loses propulsivepower because the cardiac muscle loses capacity to stretch and contract.Often, the ventricles do not adequately fill with blood betweenheartbeats and the valves regulating blood flow become leaky, allowingregurgitation or back-flow of blood. The impairment of arterialcirculation may deprive vital organs of oxygen and nutrients. Fatigue,weakness and the inability to carry out daily tasks may result. Not allheart failure patients suffer debilitating symptoms immediately. Somemay live actively for years. Yet, with few exceptions, the disease isrelentlessly progressive. As heart failure progresses, it tends tobecome increasingly difficult to manage. Even the compensatory responsesit triggers in the body may themselves eventually complicate theclinical prognosis. For example, when the heart attempts to compensatefor reduced cardiac output, it adds cardiac muscle mass causing theventricles to grow in volume in an attempt to pump more blood with eachheartbeat, i.e. to increase the stroke volume. This places a stillhigher demand on the heart's oxygen supply. If the oxygen supply fallsshort of the growing demand, as it often does, further injury to theheart may result, typically in the form of myocardial ischemia ormyocardial infarction. The additional muscle mass may also stiffen theheart walls to hamper rather than assist in providing cardiac output.Often, electrical and mechanical dyssynchronies develop within the heartsuch that the various chambers of the heart no longer beat in asynchronized manner, degrading overall cardiac function. A particularlysevere form of heart failure is congestive heart failure (CHF) whereinthe weak pumping of the heart or compromised filling leads to build-upof fluids in the lungs and other organs and tissues.

Many patients susceptible to CHF, particularly the elderly, havepacemakers, ICDs or other implantable medical devices implanted therein,or are candidates for such devices. Accordingly, it is desirable toprovide techniques for detecting and tracking CHF using such devices.One particularly effective parameter for detecting and tracking CHF iscardiac pressure, particularly LAP, i.e. the blood pressure within theleft atrium of the patient. Reliable detection or estimation of LAPwould not only permit the implanted device to track CHF for diagnosticpurposes but to also control therapies applied to address CHF such ascardiac resynchronization therapy (CRT). CRT seeks to normalizeasynchronous cardiac electrical activation and the resultantasynchronous contractions by delivering synchronized pacing stimulus tothe ventricles using pacemakers or ICDs equipped with biventricularpacing capability. The pacing stimulus is typically synchronized so asto help to improve overall cardiac function. This may have theadditional beneficial effect of reducing the susceptibility tolife-threatening tachyarrhythmias. CRT and related therapies arediscussed in, for example, U.S. Pat. No. 6,643,546 to Mathis, et atentitled “Multi-Electrode Apparatus And Method For Treatment OfCongestive Heart Failure”; U.S. Pat. No. 6,628,988 to Kramer, et al.,entitled “Apparatus And Method For Reversal Of Myocardial RemodelingWith Electrical Stimulation”; and U.S. Pat. No. 6,512,952 to Stahmann,et al., entitled “Method And Apparatus For Maintaining SynchronizedPacing”.

Reliable estimates of LAP provided by a pacemaker or ICD would alsoallow the dosing of heart failure medications (such as diuretics) to beproperly titrated so as to minimize the number of episodes of acuteheart failure decompensation. Another advantage to providing reliableestimates of LAP is that physicians are typically familiar with LAPvalues. Hence, LAP estimates could be provided to the physician viadiagnostic displays, which the physicians can then readily interpret.

However, LAP is a difficult parameter to detect since it is notclinically appealing to place a blood pressure sensor directly in theleft atrium due to the chronic risk of thromboembolic events, as well asrisks associated with the trans-septal implant procedure itself.Accordingly, various techniques have been developed for estimating LAPbased on other parameters that can be more safely sensed by a pacemakeror ICD. In this regard, a number of techniques have been developed thatuse electrical impedance signals to estimate LAP. For example, impedancesignals can be sensed along a sensing vector passing through the leftatrium, such as between an electrode mounted on a left ventricular (LV)lead and another electrode mounted on a right atrial (RA) lead. Thesensed impedance is affected by the blood volume inside the left atrium,which is in turn reflected by the pressure in the left atrium.Accordingly, there is a correlation between the sensed impedance andLAP, which can be exploited to estimate LAP and thereby also track CHF.See, for example, U.S. Provisional Patent Application No. 60/787,884 ofWong et al., entitled, “Tissue Characterization Using IntracardiacImpedances with an Implantable Lead System,” filed Mar. 31, 2006, andU.S. patent application Ser. Nos. 11/558,101, 11/557,851, 11/557,870,11/557,882 and 11/558,088, each entitled “Systems and Methods to Monitorand Treat Heart Failure Conditions”, of Panescu et al. See, also, U.S.patent application Ser. No. 11/558,194, by Panescu et al., entitled“Closed-Loop Adaptive Adjustment of Pacing Therapy based on CardiogenicImpedance Signals Detected by an Implantable Medical Device.”Particularly effective techniques for calibrating impedance-basedtechniques are set forth in: U.S. patent application Ser. No.11/559,235, by Panescu at al., entitled “System and Method forEstimating Cardiac Pressure Using Parameters Derived from ImpedanceSignals Detected by an Implantable Medical Device.”

It is desirable to provide LAP estimation techniques that do not relyonly impedance but alternatively exploit intracardiac electrogram (IEGM)signals commonly sensed by pacemakers and ICDs. Also, it is desirable toprovide techniques for automatically adjusting and controlling CRT andother forms of cardiac rhythm management therapy in response toestimated LAP so as to, e.g., mitigate the effects of CHF.

The parent application, cited above, addressed these issues by providingtechniques for estimating LAP or other cardiac performance parametersbased on measured conduction delays. In particular, using the techniquesset forth therein, LAP is estimated based interventricular conductiondelays. Predetermined conversion factors stored within the device areused to convert the various the conduction delays into LAP values orother appropriate cardiac performance parameters. The conversion factorsmay be, for example, slope and baseline values derived during an initialcalibration procedure performed by an external system, such as anexternal programmer. In some examples, the slope and baseline values areperiodically re-calibrated by the implantable device itself. Techniqueswere also set forth for adaptively adjusting pacing parameters based onestimated LAP or other cardiac performance parameters. For the sake ofcompleteness, these various techniques are all fully describedhereinbelow.

Thus, the parent application set forth techniques for estimating LAPbased on measured conduction delays within the heart. U.S. patentapplication Ser. No. 11/559,235, also cited above, set forth techniquesfor estimating LAP based on measured impedance values. Although thesetechniques are effective, it would also be desirable to combine thetechniques to use impedance values (or admittance values) to estimateconduction delays and then use the conduction delays to estimate LAP. Itis to this end that aspects of the present invention are directed. It isalso desirable to provide techniques for estimating conduction delaysfrom impedance values (or admittance values) and it is to this end thatthe present invention is primarily directed.

SUMMARY OF THE INVENTION

In accordance with an exemplary embodiment, a method and system areprovided for estimating electrical conduction delays within the heart ofa patient using an implantable medical device based on impedance oradmittance values (referred to generally herein as immittance values)measured within the patient. Briefly, a value representative ofelectrical immittance is detected within the heart of the patient. Anelectrical conduction delay within the heart of the patient is estimatedbased the value representative of immittance. That is, the deviceexploits a correlation between impedance/admittance and electricalconduction delays to estimate the conduction delays. In this regard, asthe heart tends to enlarge, particularly with heart failure progression,conduction delays tend to increase, whereas impedance values tend todecrease. Therefore, impedance (or admittance) values can be used toestimate conduction delays.

Preferably, cardiac pressure is then estimated within the patient basedon the estimated electrical conduction delay. That is, the device thenexploits a correlation between conduction delays and cardiac pressure toestimate LAP. Hence, impedance/admittance values are used to estimateconduction delays, which are in turn used to estimate LAP. In thismanner, the device can exploit techniques that estimate LAP based onconduction delays, without needing to directly measure the conductiondelays. This is particularly useful within devices that lack thecapability to directly measure conduction delays. Moreover, the deviceneed not rely on estimating LAP directly from impedance or admittance(as in some of the predecessor techniques discussed above). Within atleast some patients, calibrating a direct impedance-to-LAP conversionprocedure can be inconvenient and imprecise. By instead generatingconduction delay estimates as intermediate values, the conduction delayvalues can be used to calibrate the conversion procedure, with referenceto conduction delays obtained, e.g., using QuickOpt rapid optimizationtechniques or the like. QuickOpt techniques are described more fully inU.S. Patent Application No. 2005/0125041 of Min et al., published Jun.9, 2005, entitled “Methods for Ventricular Pacing.” QuickOpt is atrademark of St. Jude Medical.

In one example, the immittance value to be detected is an impedancevalue (Z) obtained by measuring a raw impedance signal (Z₀) along atleast one sensing vector passing through the heart of the patient andthen determining the average impedance value (Z) from the raw impedancesignal (Z₀) over, e.g., a period of sixteen seconds or about fourrespiratory cycles. Pre-determined conversion factors are then used forconverting the average impedance values to conduction delay valueswithin the patient. In an example where a single sensing vector isemployed, the conduction delays are estimated by calculating:

Delay=α+Z ² +β*Z+δ

where α, β and δ are the pre-determined conversion factors and wherein Zrepresents average impedance along a given vector passing through theheart of the patient. In an example where two sensing vectors areemployed, the conduction delays are instead estimated by calculating.

Delay=α₁ *Z ₁ ²+β₁ *Z ₁+α₂ *Z ₂ ²+β₂ *Z ₂+δ

where α₁, β₁, α₂, β₂ and δ are the conversion factors and wherein Z₁represents the average impedance along a first vector passing throughthe heart of the patient and Z₂ represents the average impedance along asecond, different vector passing through the heart of the patient. Insome implementations, three or more sensing vectors are instead used.

In another example, the immittance value to be detected is an admittancevalue (Y) obtained by measuring a raw admittance signal (Y₀) and thendetermining the average admittance value (Y) from the raw admittancesignal (Y₀) over, e.g., a period of sixteen seconds. Pre-determinedconversion factors are then used for converting the average admittancevalues to conduction delay values within the patient. In an examplewhere a single sensing vector is employed, the conduction delays areestimated by calculating:

Delay=α*Y ² +β*Y+δ

where α, β and δ are the pre-determined conversion factors and wherein Yrepresents admittance along a given vector passing through the heart ofthe patient. The conversion factors will typically be different from theones used with impedance. In an example where two sensing vectors areemployed, the conduction delays are instead estimated by calculating.

Delay=α₁ *Y ₁ ²+β₁ *Y ₁+α₂ *Y ₂ ²÷β₂ *Y ₂+δ

where α₁, β₁, α₂, β₂ and δ are the conversion factors and wherein Y₁represents the average admittance along a first vector passing throughthe heart of the patient and Y₂ represents the average admittance alonga second, different vector passing through the heart of the patient.Again, the conversion factors will typically be different from the onesuse with impedance. In some implementations, three or more sensingvectors are instead used.

The various conversion factors can be obtained in advance by, e.g.,measuring conduction delays using an external system equipped withQuickOpt while also measuring average impedance or admittance using theimplanted device. Linear regression techniques are then exploited tocalculate the appropriate conversion factors for convertingimpedance/admittance values to conduction delays.

Once the conduction delays have been estimated, LAP or other cardiacpressure values are then estimated from the delays. In one example,predetermined conversion factors are again used. The conversion factorsmay be, for example, slope and baseline values derived using linearregression techniques. Then, LAP or other cardiac pressure values areestimated within the patient by applying the conversion factors to theestimated conduction delay. For example, cardiac pressure may estimatedusing:

Cardiac Pressure=Delay*Slope+Baseline

where Delay is the estimated conduction delay and Slope and Baseline arethe conversion factors appropriate to the pressure value beingestimated.

Note that the pressure value estimated in the foregoing example (and inthe other examples described herein) is an effective intracardiacpressure (P_(eff)), not an absolute pressure. It represents the absoluteintracardiac pressure less intrathoracic pressure:

P _(eff) =P _(intracardiac) −P _(intrathoracic)

That is, the effective pressure is a type of gauge pressure. Unlessotherwise noted, all estimated cardiac pressure values discussed herein,particularly estimated LAP, are effective pressure values. In sometechniques described herein, such as techniques where the Valsalvamaneuver is exploited to reduce intracardiac pressure within the patientfor calibration purposes, the distinction between effective pressure andabsolute pressure is particularly important and effective pressureshould be used. In any case, effective pressure values are typicallymore useful from a clinical perspective than absolute pressure values.

In some implementations, therapy is then controlled based on theestimated LAP value, particularly so as to reduce LAP, or based on theestimated conduction delays. For example, pacing timing parameters suchas the atrioventricular (AV) pacing delay and the interventricular(LV-RV) pacing delay may be adjusted. Within systems equipped to providepacing at different locations within the same chamber, intraventricular(LV₁-LV₂), intra-atrial (LA₁-LA₂) delay values may additionally oralternatively be adjusted. Alternatively, multi-site pacing systems canswitch to different pacing configurations or use different pacingelectrodes in order to keep the LAP estimate within a safe orhemodynamically stable range. Preferably, the adjustments are adaptive,i.e. the adjustments are performed in a closed-loop so as to adapt theadjustments to changes in estimated LAP or changes in conduction delaysso as to optimize therapy.

By adjusting pacing parameters, the parameters can be promptly adjustedto immediately respond to changes within the heart that affectconduction delays or LAP, such as any deterioration in mechanicalsynchrony arising due to CHF, conduction defects or other ailments suchas myocardial infarction or acute cardiac ischemia. Moreover, byadaptively adjusting the pacing parameters, the direction and/ormagnitude of the adjustments need not be pre-determined. For example, itneed not be known in advance whether a particular pacing parametershould be increased or decreased in response to deterioration in LAP.Adaptive adjustment allows the direction and magnitude of anyadjustments to the pacing parameters to be automatically optimized.Thus, if an initial increase in a particular pacing parameter causes afurther deterioration in LAP, the pacing parameter may then beautomatically decreased in an attempt to improve LAP. If neither anincrease nor a decrease in a particular pacing parameter significantlyaffects LAP, then a different pacing parameter may be selected foradaptive adjustment.

The adaptive adjustment of pacing therapy using estimated conductiondelays or estimated LAP may be performed in conjunction with one or moreimpedance-based adjustments techniques, such as those set forth in theabove-cited applications of Panescu et al. For example, a valuerepresentative of mechanical dyssynchrony may be derived from averageimpedance while an estimate of LAP is derived from conduction delays,permitting both to be used in adjusting the pacing parameters. Also,impedance signals may be used to derive electrical conduction delaysfrom which LAP may be also estimated. Still further, if the implanteddevice is equipped with a sensor to directly measure another cardiacpressure value besides LAP (e.g., LV end diastolic (LV_(END)) pressure),then such pressure measurements may be used in conjunction with the LAPestimates to adjust pacing parameters so as to reduce both measures ofpressure.

In some implementations, the pacing parameters are adaptively adjustedonly when the patient is in certain predetermined states as determinedby activity sensor, posture detectors, etc. In one particular example,adaptive adjustment is only performed if the patient is at rest and in asupine posture. Adaptive adjustment may be still further limited totimes when the blood oxygen saturation (SO₂) level of the patient iswithin a certain acceptable range. Also, since conduction delays arebeing estimated (along with LAP), pacing therapy can be adjusted tocontrol the estimated delays so as to maintain the delays within a safeor stable range about a baseline. That is, both the final LAP estimateand the intermediate conduction delay estimate can be used to controlpacing therapy, track CHF, etc.

Thus, various techniques are provided for estimating conduction delaysand/or LAP for use, e.g., in automatically adjusting pacing therapy andfor detecting and tracking heart failure. Individual implantable systemsmay be equipped to perform some or all of these techniques. In someexamples, LAP is determined by combining estimates derived from thevarious individual techniques. Heart failure is then detected or trackedbased on the combined LAP estimate. Upon detecting of the onset of heartfailure, appropriate warning signals may be generated for alerting thepatient to consult a physician. The warning signals can include “tickle”warning signals applied to subcutaneous tissue and short-range telemetrywarning signals transmitted to a warning device external to the patientsuch as a bedside monitor. The warning signals, as well as appropriatediagnostic information (such as the estimated LAP values), arepreferably forwarded to the physician by the bedside monitor.

Various other forms of therapy may also be automatically applied ormodified by the implanted system in response to heart failure, dependingupon the capabilities of the system. For example, if the device isequipped to perform CRT, then CRT pacing may be initiated or otherwisecontrolled based on LAP. Also, if the implanted system is equipped witha drug pump, appropriate medications (such as diuretics) potentially maybe administered directly to the patient, depending upon the programmingof the system. Alternatively, the estimated LAP may be presenteddirectly to the patient using a handheld or a bedside monitor, so thatthe patients may utilize the estimated LAP reading to self-titrate oraldosages of heart failure medications based on a sliding scaleprescription that was provided to the patient in advance. This issimilar to the self-titration of insulin dosage based on a measuredblood sugar from a glucometer using a prescribed insulin sliding scale.

Although summarized with respect to examples where LAP is estimatedbased on conduction delays derived from immittance values, thetechniques of the invention may also be applied to estimating otherparameters from measured immittance values. For example, LV enddiastolic volume (EDV) or LV end diastolic pressure (EDP) may also beestimated, at least within some patients, based on conduction delays byusing appropriate calibration factors. Thus, a variety of cardiacchamber parameters may be estimated based on measuredimpedance/admittance values. LAP is generally preferred as it isstrongly correlated with CHF.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the invention may be more readilyunderstood by reference to the following description taken inconjunction with the accompanying drawings, in which:

FIG. 1 is a stylized representation of an exemplary implantable medicalsystem equipped with a conduction delay-based LAP estimation system;

FIG. 2 is a flow diagram providing a broad overview of conductiondelay-based cardiac pressure estimation techniques that may be performedby the system of FIG. 1:

FIG. 3 is a flow diagram summarizing an illustrative technique performedin accordance with the general technique of FIG. 2 wherein cardiacpressure is estimated from conduction delays using pre-determinedconversion factors and wherein pacing timing parameters are thenadaptively adjusted based on the estimated pressure values;

FIG. 4 is a graph illustrating a linear correlation between LAP andLV-RV delay that may be exploited by the estimation procedure of FIG. 3;

FIG. 5 is a flow diagram illustrating a particular example of theillustrative technique of FIG. 3 wherein LAP is estimated based onmeasured LV-RV delays, along with appropriate slope and baselinecalibration values, to produce a qLAP value;

FIG. 6 is a graph providing exemplary data illustrating changes overtime in qLAP values estimated within a canine test subject using thetechnique of FIG. 5;

FIG. 7 is a flow diagram illustrating a closed-loop procedure foradaptively adjusting pacing parameters based on estimated cardiacpressure values obtained in accordance with the exemplary estimationtechnique of FIG. 5;

FIG. 8 is a flow diagram illustrating an exemplary procedure forcalibrating the LV-RV delay-based LAP estimation technique of FIG. 5using calibration parameters obtained within the patient in which thesystem is implanted;

FIG. 9 is a graph illustrating a linear relationship between qLAP andLV-RV delay calibration values exploited by the calibration technique ofFIG. 8;

FIG. 10 is a flow diagram illustrating an exemplary procedure forre-calibrating the baseline value of the LV-RV delay-based LAPestimation technique of FIG. 5 using additional calibration parametersobtained within the patient while performing the Valsalva maneuver;

FIG. 11 is a flow diagram illustrating an exemplary procedure forre-calibrating both slope and baseline values of the LV-RV delay-basedLAP estimation technique of FIG. 5 using additional calibrationparameters obtained within the patient while performing the Valsalvamaneuver;

FIG. 12 is a graph illustrating a linear relationship between qLAP andLV-RV delay calibration values exploited by the re-calibration techniqueof FIG. 11, and, in particular, illustrating a zero LAP value obtainedwithin the patient during the Valsalva maneuver;

FIG. 13 is a flow diagram illustrating an exemplary procedure forcalibrating the LAP-based technique of FIG. 5 using calibrationparameters obtained from a population of test subjects;

FIG. 14 is a simplified, partly cutaway view, illustrating the pacer/ICDof FIG. 1 along with a more complete set of leads implanted in the heartof the patient;

FIG. 15 is a functional block diagram of the pacer/ICD of FIG. 14,illustrating basic circuit elements that provide cardioversion,defibrillation and/or pacing stimulation in the heart and particularlyillustrating components for estimating LAP based on conduction delaysand for adaptively adjusting pacing parameters in response thereto;

FIG. 16 is a functional block diagram illustrating components of adevice programmer of FIG. 15, and in particular illustrating aprogrammer-based LAP estimation calibration system;

FIG. 17 summarizes a technique for estimating conduction delays based onmeasured impedance values for use with the system of FIG. 1;

FIG. 18 illustrates a relationship between admittance (i.e. thereciprocal of impedance) and conduction time delays, which is exploitedby the technique of FIG. 17;

FIG. 19 illustrates changes in conduction time delays that areindicative of heart failure, which may also be exploited by thetechnique of FIG. 17;

FIG. 20 provides a stylized representation of a heart and particularlyillustrates various impedance vectors that may be exploited used tomeasure impedance for use with the technique of FIG. 17;

FIG. 21 summarizes a technique for estimating conduction delays basedmeasured immittance values for use with the system of FIG. 1, and foralso estimating LAP or other forms of cardiac pressure;

FIG. 22 illustrates a first exemplary technique for estimating LAP basedon conduction delays, wherein the delays are estimated from measuredimpedance values, in accordance with the general technique of FIG. 21;

FIG. 23 illustrates a second exemplary technique for estimating LAPbased on conduction delays, wherein the delays are estimated frommeasured admittance values, in accordance with the general technique ofFIG. 21;

FIG. 24 summarizes a calibration technique for calibrating the LAPestimation techniques of FIGS. 22-23;

FIG. 25 illustrates a functional block diagram of an alternativeimplementation of the pacer/ICD of FIG. 14, particularly illustratingcomponents for estimating conduction delays based on immittance values,for estimating LAP from the conduction delays, and for adaptivelyadjusting pacing parameters in response thereto; and

FIG. 26 is a functional block diagram illustrating components of adevice programmer of FIG. 25, and in particular illustrating animmittance-based calibration system.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following description includes the best mode presently contemplatedfor practicing the invention. The description is not to be taken in alimiting sense but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe ascertained with reference to the issued claims. In the descriptionof the invention that follows, like numerals or reference designatorswill be used to refer to like parts or elements throughout.

Overview of Implantable Medical System

FIG. 1 provides a stylized representation of an exemplary implantablepacing medical system 8 capable of detecting electrical conductiondelays within the heart of the patient and estimating LAP based on theconduction delays. To this end, implantable system 8 includes apacer/ICD 10 or other cardiac stimulation device that incorporatesinternal components (shown individually in FIG. 15, and discussed below)for detecting one or more conduction delays using electrodes mounted toa set of sensing/pacing leads 12 and for estimating LAP or other cardiacperformance parameters based on the conduction delays. In FIG. 1, onlytwo leads are shown. A more complete set of leads is illustrated in FIG.14, which is discussed below. Within many of the exemplaryimplementations described herein, LAP is estimated based on LV-RV delaysdetected by the pacer/ICD. However, other conduction delays can beexploited, alone or in combination, to estimate other cardiac pressurevalues or other cardiac performance parameters, such as EDV. LAP isemphasized as it is correlated with CHF. Predetermined conversionfactors stored within the pacer/ICD are used to convert the conductiondelays into LAP values or other appropriate cardiac chamber parameters.The conversion factors may be, for example, slope and baseline valuesderived during an initial calibration procedure performed by an externalsystem, such as an external programmer (FIG. 16.) As will be explained,the baseline value may be periodically re-calibrated by the pacer/ICDitself. The slope value is assumed to remain substantially unchangedsuch that re-calibration of the slope is typically not required.

FIG. 2 provides a broad summary of the cardiac pressure estimationtechniques that may be performed by the pacer/ICD of FIG. 1. At step 50,the pacer/ICD measures an electrical conduction delay in the heart ofthe patient where the delay is affected by cardiac pressure such as leftatrial pressure (LAP). At step 52, the pacer/ICD then estimates LAP orother suitable cardiac chamber values within the patient from theelectrical conduction delay. The pacer/ICD of FIG. 1 is also equipped totrack changes in the estimated LAP values so as to detect and track CHFand to adjust pacing parameters in an effort to mitigate CHF, such asCRT parameters. Techniques for performing CRT are discussed in thepatents to Mathis, at al., Kramer, at al., to Stahmann, et al., citedabove. Adaptively adjustment techniques set forth in the Panescu at al.patent application, “Closed-Loop Adaptive Adjustment of Pacing Therapybased on Cardiogenic Impedance Signals Detected by an ImplantableMedical Device,” cited above, may be exploited. Additionally oralternatively, the pacer/ICD may issue warning signals, if warranted.For example, if the estimated LAP exceeds a threshold indicative of CHF,warning signals may be generated to warn the patient, using either animplanted warning device 14 or an external bedside monitor/handheldwarning device 16. Internal warning device 14 may be a vibrating deviceor a “tickle” voltage device that, in either case, provides perceptiblestimulation to the patient to alert the patient so that the patient mayconsult a physician. In one example, once the tickle warning is felt,the patient positions an external warning device above his or her chest.The handheld device receives short-range telemetry signals from theimplanted device and provides audible or visual verification of thewarning signal. The handheld warning device thereby providesconfirmation of the warning to the patient along with a display of theestimated LAP, who may be otherwise uncertain as to the reason for theinternally generated warning signal. For further information regardingthis warning/notification technique, see U.S. patent application Ser.No. 11/043,612, of Kil et al., filed Jan. 25, 2005, entitled “System andMethod for Distinguishing among Ischemia, Hypoglycemia and Hyperglycemiausing an Implantable Medical Device.”

If a bedside monitor is provided, the bedside monitor provides audibleor visual alarm signals to alert the patient or caregiver, as well astextual or graphic displays. In addition, diagnostic informationpertaining to the deteriorating cardiac condition is transferred to thebedside monitor or is stored within the pacer/ICD for subsequenttransmission to an external programmer (not shown in FIG. 1) for reviewby a physician or other medical professional. The physician may thenprescribe any other appropriate therapies to address the condition. Thephysician may also adjust the operation of the pacer/ICD to activate,deactivate or otherwise control any therapies that are automaticallyapplied. The bedside monitor may be directly networked with acentralized computing system, such as the HouseCall™ system of St. JudeMedical, for immediately notifying the physician of any significantincrease in LAP. Networking techniques for use with implantable medicalsystems are set forth, for example, in U.S. Pat. No. 6,249,705 to Snell,entitled “Distributed Network System for Use with Implantable MedicalDevices.”

In addition to CRT, other forms of therapy may also be controlled by thepacer/ICD in response to changes in LAP. In this regard, if theimplanted system is equipped with a drug pump, appropriate medicationsmay be automatically administered upon detection of a significantincrease in LAP due to heart failure. For example, heart failuremedications may be delivered directly to the patient via the drug pump,when needed. Alternatively, if a drug pump is not available, the patientmay be provided with instructions depending on the estimated LAP as towhat dosage to take for various heart failure medications. Exemplaryheart failure medications include angiotensin-converting enzyme (ACE)inhibitors, diuretics, nitrates, digitalis and compounds such ascaptopril, enalapril, lisinopril and quinapril. For example, upondetection of a high LAP level, the dosage of diuretics could beincreased, either automatically via a drug pump or by sendingappropriate instructions to the bedside monitor for alerting the patientor caregiver. Depending upon the particular medication, alternativecompounds may be required for use in connection with an implantable drugpump. Routine experimentation may be employed to identify medicationsfor treatment of heart failure or other conditions that are safe andeffective for use in connection with an implantable drug pump. Dosagesmay be titrated based upon the severity of heart failure as determinedfrom LAP.

Various techniques may be employed to confirm the detection of heartfailure (or other medical conditions) made by the pacer/ICD based on theanalysis of the conduction delay before drug therapy is delivered.Exemplary impedance-based heart failure detection/evaluation techniquesare set forth in U.S. patent application Ser. No. 11/559,235, citedabove. See, also, U.S. Pat. No. 6,748,261, entitled “Implantable medicaldevice for and Method of Monitoring Progression or Regression of HeartDisease by Monitoring Interchamber Conduction Delays”; U.S. Pat. No.6,741,885, entitled “Implantable Cardiac Device for Managing theProgression of Heart Disease and Method”; U.S. Pat. No. 6,643,548,entitled “Implantable medical device for Monitoring Heart Sounds toDetect Progression and Regression of Heart Disease and Method Thereof”;U.S. Pat. No. 6,572,557, entitled “System and Method for MonitoringProgression of Cardiac Disease State using Physiologic Sensors”; andU.S. Pat. No. 6,480,733, entitled “Method for Monitoring Heart Failure”,each assigned to Pacesetter, Inc.

Hence, FIGS. 1 and 2 provide an overview of an implantable medicalsystem capable of estimating LAP based on conduction delays, adjustingpacing parameters, delivering any appropriate warning/notificationsignals, and selectively delivering medications, when warranted.Embodiments may be implemented that do not necessarily perform all ofthese functions. For example, embodiments may be implemented thatestimate LAP but do not automatically initiate or adjust therapy.Moreover, systems provided in accordance with the invention need notinclude all of the components shown in FIG. 1. In many cases, forexample, the system will include only a pacer/ICD and its leads.Implantable warning devices and drug pumps are not necessarilyimplanted. Some implementations may employ an external monitor fordisplaying warning signals without any internal warning device. Theseare just a few exemplary embodiments. No attempt is made herein todescribe all possible combinations of components that may be provided inaccordance with the general principles of the invention. In addition,note that the particular locations and sizes of the implanted componentsshown in FIG. 1 are merely illustrative and may not necessarilycorrespond to actual implant locations. Although internal signaltransmission lines provided are illustrated in FIG. 1 forinterconnecting the various implanted components, wireless signaltransmission may alternatively be employed.

Overview of Conduction Delay-Based Estimation Techniques

FIG. 3 provides an overview of LAP estimation techniques that may beperformed by the pacer/ICD of FIG. 1 or other implantable medicaldevice. At step 100, the pacer/ICD measures an electrical conductiondelay in the heart of the patient where the delay is affected by changesin chamber pressure, such as by measuring an interventricular LV-RVdelay for use in estimating LAP. An exemplary interventricularconduction path 101 along which the delay may be measured is shown inFIG. 14, which is described more fully below. The conduction pathextends through myocardial tissue between, in this particular example, apair of LV tip and ring electrodes 426 and 425 of a coronary sinus (CS)lead 424 and a paired of RV tip and ring electrodes 424 and 434 of an RVlead 430. The tip and ring electrodes 422, 423 of a RA lead 420 are alsoshown. The exemplary interventricular conduction path 101 extends, asshown, down from the LV electrodes toward the apex of the ventricles andthen in to the RV. Once the myocardium of the LV begins to depolarize inthe vicinity of the LV electrodes, electrical depolarization signalspropagate along the path ultimately triggering myocardial depolarizationwithin the RV, which is sensed using the RV electrodes. The time duringwhich the depolarization signal propagates along this (or other)interventricular paths is the conduction time delay measured at step 100of FIG. 3. It should be understood that the LV-RV delay may be negative,i.e. the RV may depolarize first, followed by the LV (with the RVdepolarizing either naturally or due to a V-pulse delivered to the RV.)That is, depolarization signals may propagate along an interventricularconduction path from the RV to LV, instead of vice versa. Herein, forclarity, when the LV-RV delay is negative, the delay is insteadtypically referred to as an RV-LV delay.

The inter-ventricular conduction time delay following the delivery of aleft ventricular pacing stimulus may be used to estimate LV size and/orLV filling pressure. At the time a pacing stimulus is delivered to theLV, the chamber is filled with blood and corresponds to the LV EDV. Thepacing stimulus will cause the LV muscle to depolarize and subsequentlycontract. While the LV depolarization occurs, the depolarizationwavefront travels across the LV toward the right ventricle andultimately causes the RV to depolarize and subsequently contract. Thedelay between the time when the LV pacing stimulus was administered andthe time when the RV depolarizes may be proportional to the LV EDV,which is also proportional to the LV EDP. LV EDP is a good estimate forLAP in the absence of significant mitral valve stenosis. Thus, theinterventricular time delay in cardiac depolarization and/or contractionfollowing a ventricular stimulus may be used, at least within somepatients, to estimate the end-diastolic ventricular filling volumeand/or filling pressure.

Moreover, the duration of the interventricular conduction delay dependslargely upon the distance over which the depolarization signaltraverses, which depends, in part, on the sizes of the chambers of theheart it passes through. As heart failure progress, pressure within theLV increases and the LV chamber often becomes distended, resulting in agenerally longer conduction time delay. Hence, there is, in at leastsome patients, a correlation between interventricular conduction timedelays and LV chamber size and LV chamber pressure. Hence, in suchpatients, there is a correlation between LV-RV delay and LV EDV and LVEDP. Likewise, as heart failure progresses, LAP increases. Accordingly,within at least some patients, there is also a correlation between LV-RVdelay and LAP. The techniques of the invention exploit this correlationto estimate LAP from the LV-RV delay. LV EDV and LV EDP may also beestimated from the LV-RV delay.

FIG. 4 illustrates data collected from a canine test subject showing thecorrelation between RV-LV delay (in msecs) and LAP (in mmHg). In thisexample, the RV-LV delay was measured based on paced RV pulses using theQuickOpt techniques, discussed below. LAP was measured using a HeartPODLAP detection device developed by Savacor Inc., now owned by St. JudeMedical. HeartPOD is a trademark of St. Jude Medical. The canine testsubject was paced via a rapid pacing protocol so as to induce andemulate heart failure, which resulted in increasing LAP values overtime. As can be seen, there is a linear correlation between LAP andRV-LV delay within this test subject, as represented by linearregression line 103. Similar correlations are present in at least some,and likely most, human heart failure patients. Based on the correlation,LAP can be estimated based on RV-LV conduction delays (or LV-RV delays),at least within patients where the correlation is present.

An LV-RV conduction delay may be measured, for example, by tracking thetime between when a V-pulse is delivered to the LV using the LV tip andring electrodes and the peak of a QRS-complex sensed within the RV usingthe RV tip and ring electrodes. An RV-LV conduction delay may bemeasured, for example, by tracking the time between when a V-pulse isdelivered to the RV using the RV tip and ring electrodes and the peak ofa QRS-complex sensed within the LV using the LV tip and ring electrodes.However, other points within the QRS-complexes might instead beemployed, such as the starting point of a complex. The peak is typicallythe easiest to detect. Also, instead of using the time at which aV-pulse is delivered, the pacer/ICD might instead detect and use thepeak of the resulting evoked response (RV). Hence, conduction delaysderived from paced events may be quantified in a variety of ways. Aswill be explained, conversion factors are used to convert the measuredtime delay into LAP or other cardiac performance values. So long as thesystem uses the appropriate conversion factors, the conduction delaysmay be measured using any suitable technique. Also, the pacer/ICD is notlimited to measuring conduction delays from paced events. As anotherexample, the conduction delay might instead be measured between the peakof a QRS-complex sensed in the LV using the tip and ring electrodes ofthe CS lead and the peak of the QRS-complex sensed within the RV, againusing tip and ring electrodes of a RV lead. Again, the conduction delaymay be quantified in a variety of ways, so long as the appropriateconversion factors are employed.

At step 102, the pacer/ICD inputs predetermined conversion factors forconverting the measured time delay to an estimate of cardiac chamberpressure, such as predetermined slope and baseline values obtained fromlinear regression analysis applied to data of the type shown in FIG. 4(though, of course, collected from human patients). Exemplarycalibration techniques for determining the conversion factors based on alinear equation derived from linear regression are discussed below. Atstep 104, the pacer/ICD then estimates LAP or other cardiac pressurevalues within the patient by applying the conversion factors retrievedfrom memory to the measured time delays or by using a neural network,linear discriminant analyzer (LDA) or other appropriate technique. Also,the pacer/ICD may classify the pressure value within discrete intervals,such as LOW, MEDIUM and HIGH. That is, the pacer/ICD need not calculatespecific values of the cardiac pressure but may instead simply determinewhether the pressure is low, medium or higher, or within otherpredetermined ranges. The discrete intervals may be used as part of aprediction model that predicts LAP trends in a discrete fashion.

When using slope and baseline conversion factors to estimate specificvalues of pressure, cardiac pressure may be generally estimated using:

Cardiac Pressure=Delay*Slope+Baseline

where Delay represents the measured conduction delay, i.e. LV-RV delay,etc., and Slope and Baseline represent the conversion factorsappropriate for use with the particular delay. This formula assumes alinear relationship between cardiac pressure and the measured conductiondelay, which is an appropriate presumption based on the particularconduction delays discussed herein, at least insofar as estimating LAPis concerned. Routine experimentation may be performed to determinewhether a linear relationship is also suitable for use in estimatingother particular cardiac chamber values, such as LVP, LV EDV or LV EDP,or is also suitable for use with other conduction delays, such as RA-LV,RA-RV, RA-LA, etc. Moreover, it should be understood that linear modelsneed not necessarily be used, i.e. more sophisticated correlation modelsmay instead by employed. Linear models are preferred in view of theirsimplicity. As noted, neural networks or LDAs may instead be employed,where appropriate.

At step 106, the pacer/ICD then adaptively adjusts pacing timingparameters in a closed loop to improve LAP or other cardiac performancevalues. For example, LV-RV delays or AV delays may be adjusted in aneffort to reduce LAP. That is, a combination of AV delay and LV-RV delayvalues are selected that yield the lowest LAP values. However, otherdelay parameters may be adjusted as well, such as inter-atrial delaysor, if the implantable system is equipped to pace at two or morelocations within a given atrial or ventricular chamber, thenintra-atrial or intraventricular delays may be adjusted. Adaptiveadjustment techniques are discussed in greater detail below. At step108, the pacer/ICD tracks CHF, controls pacing therapy (such as CRT),generates warnings and/or stores diagnostic information based onestimated LAP values or other estimated cardiac chamber parameters. Asalready explained, the warnings and/or diagnostic data can be forwardedto a physician for review. Preferably, the diagnostic data includes theestimated LAP values for physician review. This is particularlyadvantageous since physicians are typically more comfortable reviewingLAP information than raw conduction delay values.

Preferably, steps 100-108 are repeated for each heartbeat to trackchanges in LAP on a beat-by-beat basis, adjust pacing parameters, trackCHF, etc. That is, in some implementations, a near real-time LAP(t)function may be estimated so as to allow the pacer/ICD to trackbeat-to-beat changes in LAP. This allows the pacer/ICD to respondpromptly to changes within the heart of the patient. Also, thebeat-by-beat LAP estimates may be applied to a predictor or predictionmodel so as to predict changes in LAP so that therapy may be controlledin advance of unacceptably high LAP levels or so that warnings may begenerated in advance.

If the LV and RV are both being paced so that interventricularconduction delays are not readily measurable via IEGMS, the pacer/ICDmay be programmed to periodically suspend RV pacing (or LV pacing) so asto permit at least a few intrinsic ventricular depolarizations so thatthe conduction delays can be measured. Alternatively, the electricalconduction delay technique of the invention may be used in conjunctionwith impedance-based mechanical delay techniques, which can deriveestimates of LAP during those heartbeats when LV-RV conduction delaysare not readily measurable. See, for example, U.S. patent applicationSer. No. 11/558,194, by Panescu et al., cited above. In general, theconduction delay-based LAP estimation techniques of the invention can becombined with a variety of other LAP estimation techniques to derive afinal estimate of LAP. Still further impedance signals may be analyzedto determine the electrical conduction delays from which cardiacpressure may then be estimated using appropriate conversion factors. Inthis regard, it is known in the art that electrical impedance changesmay be indicative of changes in heart chamber dimensions. See, e.g.,U.S. Pat. No. 5,003,976 to Alt. Alt describes that analyzing theimpedance between two intracardiac electrodes may be used to determinechanges in cardiac chamber volumes. As already explained, changes inchamber volume also affect conduction delays, allowing impedance signalsto be used to detect conduction delays, particularly in circumstancewhere such delays cannot readily be determined from IEGMs.

Although the examples described herein are primarily directed toestimating LAP, other cardiac performance parameters may alternativelybe estimated, such as LV EDV, LV EDP, RVP, RAP, etc., by usingappropriate conversion factors in combination with appropriateconduction delays. Otherwise routine experimentation may be performed toidentify particular parameters detectable using the techniques of theinvention and the appropriate conduction delays and conversion factors.In some cases, a linear conversion may not be suitable and algorithmsthat are more sophisticated may be required to convert conduction delaysinto parameter estimates. In some cases, multiple conduction delays maybe required to properly estimate a particular parameter. That is,multiple conduction delays may be measured using different electrodes soas to permit the pacer/ICD to estimate chamber pressures and volumeswithin different chambers of the heart, assuming appropriate conversionvalues have been determined and calibrated. To this end, the implantedsystem may be equipped, e.g., with multiple electrodes per lead or withmultiple leads per chamber. Unipolar, bipolar or cross-chamber sensingsystems may be employed, where appropriate.

Turning now to FIGS. 5-13, various illustrative embodiments will bedescribed in greater detail.

Exemplary LAP Estimation Techniques

FIG. 5 provides an LV-RV delay-based LAP detection example whereinQuickOpt procedures were used for ascertaining the conduction delays. Atstep 200, the pacer/ICD measures the LV-RV delay (D_(LV-RV)) based ontime delay between an LV-pulse and an RVQRS-complex or between a pair ofLV and RVQRS-complexes using QuickOpt or other suitable delay detectiontechnique. The QuickOpt technique is discussed in U.S. PatentApplication No. 2005/0125041, cited above. For the sake of completeness,pertinent portions of the QuickOpt code are provided in the attachedappendix (Appendix A). The example of Appendix A primarily operates toset RV thresholds. However, the LV-RV delay may be obtained usinginformation generated by the code. That is, in the code, “ndx_lv” is thelocation of the LV QRS. “ndx_rv” is the location of the RV QRS. Hence,the LV-RV delay may be obtained by subtracting ndx_rv from ndx_lv (orvice versa).

At step 202, the pacer/ICD inputs the particular slope and baselinevalues (Slope_(LAR/LV-RV) and Baseline_(LAP/LV-RV)) for converting thedelay value (D_(LV-RV)) into an estimate of LAP (denoted qLAP_(LV-RV)).The slope and baseline values (which also may be referred to as gain andoffset values) are predetermined conversion values that the pacer/ICDretrieves from memory. Calibration techniques for initially deriving theconversion values will be discussed below with reference to FIGS. 8-13.At step 204, the pacer/ICD estimates LAP by applying the slope andbaseline values to the delay value:

qLAP_(LV-RV) =D _(LV-RV)*Slope_(LAP/Lv-RV)+Baseline_(LAP/LV-RV)

As indicated by step 206, the pacer/ICD repeats for each heartbeat totrack qLAP(t). The LV-RV subscript is applied to qLAP to indicate thatthis estimate is made based on LV-RV delays (rather than some otherconduction delay value.) The LAP/LV-RV subscript is applied to Slope andBaseline to indicate that these conversion factors are appropriate foruse in estimating LAP based on LV-RV delays (rather than some othercardiac chamber parameter estimated from some other conduction delayvalue.)

FIG. 6 illustrates qLAP_(LV-RV) values obtained within the same caninetest subject of FIG. 4 showing changes over time as heart failure isinduced, Light-shaded dots 207 are qLAP_(LV-RV) values calculated asdescribed herein. The darker-shaded dots 209 are actual LAP valuesmeasured using the HeartPOD system, discussed above, which includes anLAP sensor. As can be seen, the qLAP_(LV-RV) values correlate fairlywell with the HeartPOD values, verifying that the estimation iseffective. (The qLAP_(LV-RV) values are not necessarily identical to theactual LAP values since qLAP_(LV-RV) merely provides an estimate of LAPand not a precise value.) The graph also shows zLAP values (representedby way of the light-shaded curve 211), as well as a six point movingaverage of zLAP (represented by way of the dark-shaded curve 213). ThezLAP values were obtained using the impedance-based LAP estimationdetection techniques set forth in U.S. patent application Ser. No.11/559,235, cited above. (More generally, the techniques describedtherein are “admittance-based.”) As can be seen, the zLAP estimatesdiverge from qLAP_(LV-RV) values and from the true LAP values during thefirst couple of weeks of data. This is due to healing in and around therecently implanted electrodes, which affects impedance measurements.Hence, one advantage of the conduction delay-based techniques describedherein (i.e. qLAP techniques) is that reliable estimates can be achievedeven during the first few weeks following lead implant. (Note that thefigure also provides the slope and baseline values used in calculatingzLAP (based on admittance) and qLAP_(LV-RV) (based on the LV-RVconduction delay).)

Returning to FIG. 5, at step 208, the pacer/ICD adjusts the timingdelays (such as the LV-RV and AV delays) in an effort reduceqLAP_(LV-RV) so as to mitigate CHF or other heart ailments. In thisregard, the various pacing timing parameters noted above may beadaptively adjusted. That is, typically, at least the AV and LV-RVtiming parameters are adjusted. Advantageously, the direction andmagnitude of the adjustment need not be known in advance. Rather, thepacer/ICD makes an incremental adjustment in one timing parameter in onedirection, then determines whether the adjustment improved qLAP_(LV-RV)or not. If an improvement is gained, the pacer/ICD makes an additionalincremental adjustment in that timing parameter in that same directionin an attempt to achieve still further improvement. If the adjustmenthas an adverse effect on qLAP_(LV-RV), the pacer/ICD makes anincremental adjustment in the same timing parameter but in the oppositedirection in an attempt to achieve an improvement in qLAP_(LV-RV). Themagnitudes of the adjustments are adaptively varied so as to furtheroptimize the parameter. If the initial adjustment had no effect, thepacer/ICD selects a different timing parameter to adjust. Once aparticular parameter is optimized, the pacer/ICD can select a differentparameter. For example, once AV delay has been optimized, the VV pacingdelay may then be optimized. The range within which the parameters areautomatically adjusted can be restricted via device programming toensure that the parameters remain within acceptable bounds.

Care should be taken when optimizing or adapting pacing parameters whenthe parameter that is to be optimized is the parameter that is initiallymeasured and used to estimate qLAP. Such closed loop feedback techniquesare not precluded but it is often appropriate to restrict the rangethrough which the parameters are automatically adjusted or by providingother suitable feedback control techniques. For example, insofar asoptimizing or adapting VV delays based on qLAP values derived from LV-RVdelays are concerned, the VV delay may be adjusted from a qLAP valueestimated based on LV-RV delays by defining suitable adjustmentcriteria. This is generally equivalent to a closed loop system where thefeedback variable is optimized to a pre-established criterion (e.g. bykeeping qLAP to less than 25 mmHg.). This is discussed more fully below.Similarly, qLAP could be used to adjust pacing sites to reach apre-established estimated LAP goal.

FIG. 7 provides an exemplary closed-loop adjustment procedure whereinpacing parameters are adaptively adjusted so as to reduce a qLAP butonly under certain conditions. Beginning at step 215, the pacer/ICDdetects detect patient activity level, patient posture, blood oxygensaturation values (SO₂) and heart rate. Patient activity may be detectedusing an accelerometer or other physical activity sensor mounted withinthe pacer/ICD itself or positioned elsewhere within the patient.Depending upon the implementation, the physical activity sensor may beemployed in conjunction with an “activity variance” sensor, whichmonitors the activity sensor diurnally to detect the low variance in themeasurement corresponding to a rest state. For a complete description ofan activity variance sensor, see U.S. Pat. No. 5,476,483 to Bornzin etal., entitled “System and Method for Modulating the Base Rate duringSleep for a Rate-Responsive Cardiac Pacemaker.” Techniques for detectingpatient posture or changes in posture are set forth in U.S. patentapplication Ser. No. 10/329,233, of Koh et al., entitled “System andMethod for Determining Patient Posture Based On 3-D Trajectory Using anImplantable Medical Device”. Other techniques are set forth in U.S. Pat.No. 6,044,297 to Sheldon, et al. “Posture and Device Orientation andCalibration for Implantable Medical Devices.” Techniques for detectingSO₂ are described in U.S. Pat. No. 5,676,141 to Hollub, entitled“Electronic Processor for Pulse Oximeters.” Depending upon theparticular application, either arterial SO₂ (i.e. SaO₂), or venous SO₂(i.e. SvO₂), or both, may be detected and exploited. Heart rate may bederived from an IEGM.

At step 217, the pacer/ICD determines whether all of the following aretrue: (1) the patient is at rest and has been at rest for somepredetermined amount of time, based on patient activity; (2) the postureis supine; (3) SO₂ is within an acceptable predetermined rangeconsistent with patient rest; and (4) heart rate is within an acceptablepredetermined range consistent with rest (such as a heart rate below 80beats per minute (bpm)). If these conditions are met, the pacer/ICDproceeds to steps 219-223 to adaptively adjusting the pacing parameters.That is, at step 219, the pacer/ICD measures conduction delay values,such as LV-RV delays. At step 221, the pacer/ICD calculates qLAP fromthe measured delay using the techniques discussed above. At step 223,the pacer/ICD adaptively adjusts pacing parameters such as CRT timingparameters in an effort to maintain qLAP within a predeterminedacceptable range and also records the latest timing parameters and qLAPvalues for subsequent physician review. For example, the pacer/ICD maybe programmed to attempt to maintain qLAP within the range of 10-15mmHg. In one example, if qLAP is initially found to be within thatrange, no pacing parameter adjustments are made. However, if qLAP isfound to be in the range of 15-25 mmHg, then CRT parameter are adjustedin an attempt to reduce qLAP to within 10-15 mmHg. If qLAP is found toexceed 25 mmHg, then the pacer/ICD may be programmed to warning thepatient (and/or the appropriate medical personal) and/or to initiateappropriate therapy. For example, if a drug pump is provided, thepacer/ICD may control the drug pump to deliver diuretics or othermedications directed to reducing LAP (assuming such medications areavailable and have been found to be safe and effective for delivery viaan implantable drug pump.) If no drug pump is provided, the pacer/ICDmay relay instruction signals to the patient (and/or appropriate medicalpersonnel) to direct the patient to take suitable medications. In thismanner, medications directed to reducing LAP may be titrated.Alternatively, warnings may simply be generated that direct the patientto see his or her physician. The following summarizes one exemplaryimplementation of these strategies:

-   -   If qLAP in healthy range (e.g. 10 mmHg<qLAP<15 mmHg), continue        normal pacing    -   If qLAP above healthy range (e.g. qLAP>15 mmHg), adaptively        adjust pacing timing parameters (including, e.g., CRT        parameters) in an effort to return qLAP to healthy range; record        latest timing parameters and qLAP value for subsequent physician        review    -   If qLAP is significantly above healthy range (e.g. qLAP>25        mmHg), generate warnings and/or instruct patient to take        medications    -   If qLAP below healthy range, (e.g. qLAP, 10 mmHg), generate        warnings of low LAP

Still further, any CRT adjustments may be made based not only on qLAPbut on other parameters as well. For example, adjustments may be made soas to maintain qLAP within a given range while also maintaining certainIEGM morphological parameters (such as P-wave width) within a certainrange. As can be appreciated a wide range of feedback strategies andtechniques may be exploited.

Processing then returns to step 215 and, so long as the conditions ofstep 217 are still met, the pacer/ICD will continually and incrementallyadjust the pacing parameters using the adaptive procedure. This helpsensure that adjustments are made while the patient is in a particularresting state so that changes to qLAP due to factors other than thechanges in the pacing parameters (such as patient activity) will notadversely affect the adaptive procedure. By looking at just qLAP values,which can be calculated fairly quickly, the procedure can typically beperformed in near real-time. Once the patient becomes active again,further adaptive adjustments to pacing parameters are suspended untilthe patient is again at rest. Note that the list of patient statusconditions in step 217 is merely exemplary. In other examples, more orfewer conditions may be used. For example, in other implementations, thepatient need not necessarily be supine. Also, if the patient is subjectto AF, the acceptable heart rate range may be expanded or that conditioneliminated entirely so that frequent episodes of AF do not preventadaptive adjustment of the pacing parameters.

Various additional techniques and strategies for adaptively optimizingpacing parameters may be employed, where appropriate, to supplement orenhance the techniques described herein. Examples are set forth in U.S.patent application Ser. No. 11/231,081, filed Sep. 19, 2005, of Turcott,entitled “Rapid Optimization of Pacing Parameters”; U.S. patentapplication Ser. No. 11/199,619, filed Aug. 8, 2005, of Gill et al,entitled “AV Optimization Using Intracardiac Electrogram”; U.S. patentapplication Ser. No. 11/366,930, of Muller et al., filed Mar. 1, 2006,entitled “System and Method for Determining Atrioventricular PacingDelay based on Atrial Repolarization”; U.S. patent application Ser. No.10/928,586, of Bruhns et al., entitled “System and Method forDetermining Optimal Atrioventricular Delay based on Intrinsic ConductionDelays”, filed Aug. 27, 2004; and U.S. Pat. No. 6,522,923 to Turcott,entitled “Methods, Systems and Devices for Optimizing Cardiac PacingParameters Using Evolutionary Algorithms.” See, also, the adaptiveadjustment techniques described in the above-cited patent application ofPanescu at al. (Ser. No. 11/558,194).

The locations of pacing sites may also be adaptively adjusted based onqLAP. In one particular example, the pacer/ICD is equipped with Nelectrodes in the RV, where N is an arbitrary number of electrodes. Thepacer/ICD calculates qLAP when unipolar pacing is performed using eachRV electrode, i.e. RV₁—case, RV₂—case, RV₃—case, etc. The pacer/ICD thenselects the particular RV electrode that achieves the lowest value ofqLAP for use in performing further pacing. Once optimal pacing sites arechosen, CRT timing parameters may be optimized using the techniquesabove for use with that particular pacing site. Similarly, the LV leadmay carry multiple CRT pacing electrodes. In a similar fashion, optimalpacing configurations can be selected from the electrodes on the LVlead. Yet similarly, combined RV and LV pacing configurations may beselected to reduce qLAP. Alternatively, all these pacing electrodes canbe separately, or individually, distributed on endocardial, epicardialor within myocardial tissue. The electrodes can be carried on separateleads, on multiple leads or implanted individually. Note that, wheneverswitching between pacing electrodes, new conversion factors will need tobe applied/available. Accordingly, the pacer/ICD will need to havesufficient resources to store the many conversion factors and to keeptrack of which ones are well-calibrated and which ones are inaccurate(or otherwise not useable).

Calibration Techniques

A variety of techniques may be used to initially determine andsubsequently adjust the conversion values (Slope_(LAP/LV-RV) andBaseline_(LAP/LV-RV)), i.e. to calibrate the delay-based estimationtechnique of FIG. 5. FIG. 8 summarizes a technique wherein calibrationis performed based on calibration values obtained within the particularpatient in which the pacer/ICD is implanted. That is, the conversionvalues are optimized for use with the particular patient. The procedureof FIG. 8 is performed by a physician during the implant procedure ofthe pacer/ICD while venous access is readily available and a Swan-Ganzcatheter can be easily inserted. The procedure in FIG. 8 may be repeatedor performed alternatively at a follow-up session after implantation ofthe pacer/ICD. At step 210, an external calibration system (such as theexternal programmer of FIG. 15) detects or inputs a first delaycalibration value (D_(LV-RV/1)) and a corresponding first LAPcalibration value (LAP₁) measured while the patient is at rest.Preferably, the delay value (D_(LV-RV/1)) is detected by the pacer/ICDitself using its leads and its internal detection circuitry, thentransmitted to the external system. Simultaneously, LAP₁ is detectedusing, e.g., a Swan-Ganz catheter to measure PCWP. The LAP value is alsorelayed to the external programmer.

At step 212, detects a second delay calibration value (D_(LV-RV/1)) anda corresponding second LAP calibration value (LAP₂) measured at a timewhen the patient is subject to a condition significantly affecting LAPso that LAP₂ differs substantially from LAP₁. For example, the physicianmay have the patient perform isometric muscle contractions, particularusing thoracic muscles, so as to change LAP within the patient.Alternatively, the physician may administer vasodilatation orvasoconstriction medications, so as to change LAP, or may temporarilyreprogram the pacer/ICD to perform rapid pacing, which also changes LAP.Still further, the physician may have the patient perform the Valsalvamaneuver, which reduces effective LAP secondary to reduced venousreturn, or may instead have the patient perform the handgrip maneuver,which tends to increase LAP. (The Valsalva maneuver occurs when apatient forcibly exhales for about 15 seconds against a fixed resistancewith a closed glottis while contracting the abdominal muscles. A suddentransient increase in intra-thoracic and intra-abdominal pressuresoccurs, which tends to empty the chambers of the heart of blood, suchthat within 1 to 2 seconds (phase I of the Valsalva maneuver) theeffective right atrial and right ventricular pressures drop to zero,while following 5 seconds (Late phase II) the effective left atrial andleft ventricular pressures tend to reach zero.) Again, the conductiondelay value is detected by the pacer/ICD itself then transmitted to theexternal system.

Thus, after step 212, the external system has obtained at least twopairs of calibration values (LAP₁, D_(LV-RV/1) and LAP₂, D_(LV-RV/2))where the LAP values differ substantially from one another. Since theLV-RV conduction delay varies due to changes in LV chamber volume thatcorrelate with changes in the LAP, the delay values likewise differ fromone another, permitting reliable calculation of the slope and baselinevalues.

At step 214, the external system calculates Slope_(LAP/LV-RV) using:

Slope_(LAP/LV-RV)=(LAP₂−LAP₁)/(D _(LV-RV2) −D _(LV-RV/1)).

At step 216, the external system calculates Baseline_(LAP/LV-RV) using:

Baseline_(LAP/LV-RV)=LAP₁−Slope_(LAP/LV-RV/1) *D _(LV-RV/1)

These values are then transmitted to the pacer/ICD for storage thereinfor use in estimating LAP based on newly detected delay values using thetechnique of FIG. 5. Preferably, qLAP values provided by the pacer/ICDare compared with LAP values detected using the Swan-Ganz catheter toverify that the estimation system of the pacer/ICD has been properlycalibrated.

As noted, LV-RV conduction delays are not the only delays that might beused in estimating LAP or other cardiac pressure values. Hence, thefirst and second delay calibration values are also more generallyreferred to herein as D₁ and D₂. The external system calculates Slopeusing:

Slope=(Pressure₂−Pressure₁)/(D ₂ −D ₁).

The external system calculates Baseline using:

Baseline=Pressure₁−Slope*D ₁.

FIG. 9 illustrates an exemplary pair of calibration values 220, 222,along with exemplary slope 224 and baseline values 226 derived therefromusing the technique of FIG. 8. Although only two pairs of calibrationvalues are used in the example of FIG. 8, it should be understood thatadditional pairs of calibration values might be obtained. Linearregression techniques may be used to derive slope and baseline valuesfrom a plurality of pairs of calibration values. Also, as indicated bystep 218, the recalibration procedure of FIG. 8 can be repeatedperiodically (such as during subsequent follow-up sessions with thepatient) to update both the slope and baselines values to respond tochanges, if any, that may arise within the patient, perhaps due toscarring near the sensing electrodes. Alternatively, a re-calibrationtechnique may be performed by the pacer/ICD itself that re-calibratesonly the baseline value. This is summarized in FIG. 10.

FIG. 10 illustrates a recalibration procedure performed by the pacer/ICDto re-calibrate the baseline value. The procedure exploits theassumption that the slope value, once calculated for a particularpatient, typically does not change significantly within the patient.This allows the baseline value to be re-calibrated independently of theslope value. At step 228, the pacer/ICD detects an additional delaycalibration value (D_(LV-RV/N)) while the patient performs the Valsalvamaneuver. As already explained, during the Valsalva maneuver effectiveLAP drops to zero or near zero. Hence, a separate measurement ofeffective LAP is not required. Under the assumption that effective LAPdrops to zero at the time when the additional delay value (D_(LV-RV/N))is measured, the baseline value can be re-calculated, at step 230, basedon the previous slope and the new delay value (D_(LV-RV/N)) using:

New_Baseline_(LAP/LV-RV)=−Slope_(LAP/LV-RV) *D _(LV-RV/N).

A particularly attractive feature of this recalibration procedure isthat it is non-invasive and can be performed in the ambulatory settingin the physician's office during a routine follow-up visit. Preferably,re-calibration is performed while the patient is clinically stable.

In some patients with diastolic heart failure and poor left ventricularcompliance who may have higher cardiac filling pressures (PCWP>20 mmHg)even when well compensated, the effective LAP may not drop completely tozero during a Valsalva maneuver and a correction term may need to beapplied to account for this possibility. (See, for example, FIG. 5 ofU.S. Patent Application 2004/0019285 of Eigler, et al., entitled“Apparatus for Minimally Invasive Calibration of Implanted PressureTransducers,” which is incorporated by reference herein in itsentirety.)

In order to determine whether a particular patient requires such acorrection term, a third measurement of the conduction delay (D₃) duringthe original calibration procedure FIG. 8 should be obtained while thepatient is performing the Valsalva maneuver. This assumes that D₁ and D₂were not obtained during a Valsalva maneuver. The correction term(qLAP_(VALSALVA)) is simply computed using:

qLAP_(VALSALVA) =D ₃*Slope_(LAP/LV-RV)+Baseline_(LAP/LV-RV)

wherein qLAP_(VALSALVA) is an effective LAP pressure value. Ideally, ifthe blood volume inside the left atrium significantly decreases duringthe Valsalva maneuver, then qLAP_(VALSALVA) will be near zero. Step 230may alternatively be computed using:

New_Baseline_(LAP/LV-RV) =qLAP_(VALSALVA)−Slope_(LAP/LV-RV) *D _(N).

The response of intracardiac pressures to the Valsalva is discussed inMcClean et al., “Noninvasive calibration of cardiac pressure transducersin patients with heart failure: An aid to implantable hemodynamicmonitoring and therapeutic guidance”, Journal of Cardiac Failure, Vol.12 No. 7 2006, pp 568-576. It is described therein that during theValsalva maneuver the effective PCWP reduces nearly to zero as describedabove. A similar observation was observed for other chambers of theheart. In particular, the effective residual pressure within a specificcardiac chamber (P_(eff)) was computed as the difference between themeasured intracardiac pressure (P_(intracardiac)) and the simultaneousintrathoracic or airway pressure (P_(airway)) averaged over the timeinterval from 5 to 10 seconds after the initiation of the Valsalvamaneuver (Late phase II). The effective intracardiac pressure (P_(eff))is computed using:

P _(eff) =P _(intracardiac) −P _(airway)

where (P_(airway)) is detected, e.g., using an external pressuredetection system. See, for example, the upper airway apparatus of FIG. 2of U.S. Patent Application 2004/0019285 of Eigler, at al., cited above.Thus, in order to estimate the effective LAP (LAP_(eff)) during theValsalva maneuver one may obtain this measurement directly by computingaverage of the difference between the PCWP and the simultaneous airwaypressure over the interval from 5 to 10 seconds following the initiationof the Valsalva maneuver (late Phase II). This may be written morespecifically as:

LAP_(eff)=PCWP−P _(airway)

and LAP_(eff) may be used alternatively as the correction term describedabove.

The new baseline value is then used when converting additionalconduction delay values to effective qLAP values (step 204 of FIG. 5.)As indicated by step 232, the pacer/ICD can periodically recalibrate itsestimation system by repeating the procedure to calculate newBaseline_(LAP/LV-RV) values while assuming Slope_(LAP/LV-RV) remainssubstantially constant and using the correction term where appropriate.

In practice, the procedure of FIG. 10 may be initiated by periodicallyhaving the pacer/ICD transmit a signal to the bedside monitor providinginstructions to the patient to perform the Valsalva maneuver. Thepacer/ICD detects the new conduction delay value during the Valsalvamaneuver and updates the baseline value. The pacer/ICD may beadditionally programmed to verify that the patient actually performedthe maneuver by, e.g., analyzing changes in respiration (as detectedusing otherwise conventional respiration detection techniques) to verifythat respiratory patterns consistent with the Valsalva maneuver occur.The pacer/ICD can also time its detection of the additional conductiondelay value based on the respiratory signals to help ensure that the newconduction delay value is measured at a point when effective LAP isexpected to be zero. Alternatively, the re-calibration technique may beperformed only under the supervision of a physician or other clinicianduring a follow-up session with the patient. Still, the re-calibrationprocedure eliminates the need to directly measure effective LAP duringthe follow-up using a Swan-Ganz catheter. The catheter is only employedduring the original calibration procedure. Thus, FIG. 10 illustrates atechnique wherein the baseline value is re-calibrated by the pacer/ICDunder the assumption that slope does not change by exploiting theValsalva maneuver. The Valsalva maneuver may also be exploited tore-calibrate both slope and baseline, if needed within a particularpatient. This is illustrated in FIGS. 11 and 12.

FIG. 11 summarizes a recalibration procedure performed by the pacer/ICDto re-calibrate both the slope and baseline values. The procedure can beused in patients where the slope value changes. At step 234, thepacer/ICD inputs the original conduction delay calibration value(D_(LV-RV/1)) and effective pressure calibration value (LAP₁) originallymeasured following device implant (FIG. 8) or during a previouscalibration procedure. The assumption is that LAP₁ is unchanged from theprevious calibration procedure. At step 236, the pacer/ICD detects anadditional conduction delay calibration value (D_(LV-RV/N)) while thepatient performs the Valsalva maneuver. As already noted, during theValsalva maneuver effective LAP typically drops to at or near zero andso separate measurement of effective LAP is not required. Rather, it isassumed that effective LAP is zero when the additional conduction delayvalue (D_(LV-RV/N)) is measured, thus allowing the slope to bere-calculated, at step 238, using:

New_Slope_(LAP/LV-RV)=−LAP₁/(D _(LV-RV/N) −D _(LV-RV/1)).

Once the new slope value is calculated, the new baseline value can becalculated, at step 240, using:

New_Baseline_(LAP/LV-RV)=−New_Slope_(LAP/LV-RV) *D _(LV-RV/N).

More generally:

Slope=−Pressure₁/(D _(N) −D ₁) and

Baseline=−Slope*D _(N)

The new slope and baseline values are then used when convertingadditional conduction delay values to effective qLAP values (step 206 ofFIG. 5.) As indicated by step 242, the pacer/ICD can periodicallyrecalibrate its estimation system by repeating the procedure tocalculate new Baseline_(LAP/LV-RV) and Slope_(LAP/LV-RV) values andusing the correction term where appropriate. As with the procedure ofFIG. 10, the procedure of FIG. 11 may be initiated by periodicallyhaving the pacer/ICD transmit a signal to the bedside monitor providinginstructions to the patient to perform the Valsalva maneuver or theprocedure may be performed under the supervision of a physician or otherclinician.

FIG. 12 illustrates an exemplary pair of calibration values 244, 246,along with exemplary slope 248 and baseline values 250 derived therefromusing the technique of FIG. 11. The first pair of calibration values 244is obtained following implant. The second pair of calibration values 246is obtained during the re-calibration procedure while the patientperforms the Valsalva maneuver. Since the Valsalva maneuver is beingperformed, the effective LAP value of the second pair of calibrationvalues 246 is zero and so the pressure need not be measured. Theconduction delay value of the second pair along with the pressure andconduction delay values of the first pair are used to calculate the newslope 244 and baseline values 250 using the equations of FIG. 11.

Turning now to FIG. 13, techniques are summarized for calibrating orre-calibrating the conduction delay-based estimation procedure based ondata from a population of human patients or human test subjects. In thespecific example of FIG. 13, data is obtained from a plurality of testpatients subject to various stages of heart failure and have various LAPvalues. Beginning at step 252, the external calibration system detectsor inputs a plurality of conduction delay calibration values(D_(LV-RV/1-N)) and corresponding LAP calibration values (LAP_(1-N))within N different human test subjects equipped with pacer/ICDs, somehealthy, others suffering differing stages of heart failure, i.e.differing levels of severity of heart failure. The conduction delayvalues are detected by the pacer/ICDs of the test subjects, then relayedto the external calibration system. The LAP values may be obtained usingSwan-Ganz catheters or the like. Since the test subjects exhibitdiffering stages of heart failure, differing values of LAP are therebyexhibited. At step 254, the external system then calculatesSlope_(LAP/LV-RV) and Baseline_(LAP/LV-RV) values using linearregression based on the conduction delay calibration values(D_(LV-RV/1-N)) and the LAP calibration values (LAP_(1-N)). At step 256,the external system then stores the Slope_(LAP/LV-RV) andBaseline_(LAP/LV-RV) values within individual pacer/ICDs of individualpatients for use therein. By obtaining data from a population of testsubjects, the slope and baseline values are therefore likely to beeffective within a wide range of patients. In some patients, thesevalues may be sufficient to provide an adequate estimate of LAP. Inother patients, these values may be used as starting points for furtherre-calibration. For example, the slope value obtained via the techniqueof FIG. 13 may be used within a wide range of patients along withpatient-specific baseline values obtained using the baseline-onlyre-calibration procedure of FIG. 10.

Thus, a variety of techniques for calibrating the procedure, estimatingLAP and then tracking heart failure are provided. These may besupplemented by using other non-conduction delay-based cardiac pressuredetection and heart failure detection techniques. In someimplementations, before an alarm is activated or any therapy isautomatically delivered, the pacer/ICD employs at least one otherdetection technique to corroborate the detection of heart failure.Techniques for detecting or tracking heart failure are set forth thefollowing patents and patent applications: U.S. Pat. No. 6,328,699 toEigler, et al., entitled “Permanently Implantable System and Method forDetecting, Diagnosing and Treating Congestive Heart Failure”; U.S. Pat.No. 6,970,742 to Mann, et al., entitled “Method for Detecting,Diagnosing, and Treating Cardiovascular Disease”; U.S. Pat. No.7,115,095 to Eigler, at al., entitled “Systems and Methods forDetecting, Diagnosing and Treating Congestive Heart Failure”; U.S.patent application Ser. No. 11/100,008, of Kil et al., entitled “SystemAnd Method For Detecting Heart Failure And Pulmonary Edema Based OnVentricular End-Diastolic Pressure Using An Implantable Medical Device”,filed Apr. 5, 2005; U.S. patent application Ser. No. 11/014,276, of Minet al., entitled “System And Method For Predicting Heart Failure BasedOn Ventricular End-Diastolic Volume/Pressure Using An ImplantableMedical Device”, filed Dec. 15, 2004; U.S. patent application Ser. No.10/810,437, of Bornzin et al., entitled “System and Method forEvaluating Heart Failure Based on Ventricular End-Diastolic Volume Usingan Implantable Medical Device,” filed Mar. 26, 2004 and U.S. patentapplication Ser. No. 10/346,809, of Min et al., entitled “System andMethod for Monitoring Cardiac Function via Cardiac Sounds Using anImplantable Cardiac Stimulation Device,” filed Jan. 17, 2003. See also:U.S. Pat. No. 6,572,557, to Tchou, et al., cited above. U.S. Pat. No.6,645,153, to Kroll et al., entitled “System and Method for EvaluatingRisk of Mortality Due To Congestive Heart Failure Using PhysiologicSensors”, and U.S. Pat. No. 6,438,408 to Mulligan et al., entitled“Implantable Medical Device For Monitoring Congestive Heart Failure.”Also, other calibration procedures may potentially be exploited inconnection with the calibration techniques described herein. See, forexample, U.S. Patent Application 2004/0019285 of Eigler, et al., citedabove, particularly the various linear regression techniques discussedtherein. Also, see the calibration procedures set forth in U.S. patentapplication Ser. No. 11/559,235, by Panescu et al., entitled “System andMethod for Estimating Cardiac Pressure Using Parameters Derived fromImpedance Signals Detected by an Implantable Medical Device,” citedabove.

The examples above primarily pertain to estimating LV-RV delays.However, as already noted, other conduction delays can be used toestimate LAP. In general, any conduction delay that is affected by aparticular cardiac pressure parameter might be exploited to estimatethat cardiac pressure parameter. For example, LAP may also be estimatedfrom AV delays. AV may be determined in much the same manner as LV-RVdelays are determined (i.e. paced on pacer or sensed atrial andventricular events.) Also, the morphology of the P-wave may be exploitedto estimate AV delays (such as its shape or width). Typically, the widerthe P-wave, the longer the AV delay. The narrower the P-wave, theshorter the AV delay. The morphology of atrial evoked responses may alsobe exploited to estimate AV delay. The QuickOpt code of the appendix maybe modified as needed to provide these parameters. The following is alist of parameters that generally can be exploited to estimate LAP orother cardiac pressure parameter and which can be obtained from theQuickOpt code of the appendix or from modified versions thereof:

A sense and A pace wave duration (indicates LA dilation and qLAP)

V sense: RV-LV conduction delay

RV pace-LV pace delay; LV-RV pace delay; or differences therebetween,including any appropriate correction terms.

PR and AR: atrio-ventricular delays.

RV-LV pace delay minus pacing latency (which is an alternative to Vsense that tests for heart block in patients.)

Although primarily described with respect to examples having apacer/ICD, other implantable medical devices may be equipped to exploitthe techniques described herein, For the sake of completeness, anexemplary pacer/ICD will now be described, which includes components forperforming the functions and steps already described. Also, an exemplaryexternal programmer will be described, which includes components forperforming the calibration steps already described.

Exemplary Pacer/ICD

With reference to FIGS. 14 and 15, a description of an exemplarypacer/ICD will now be provided. FIG. 14 provides a simplified blockdiagram of the pacer/ICD, which is a dual-chamber stimulation devicecapable of treating both fast and slow arrhythmias with stimulationtherapy, including cardioversion, defibrillation, and pacingstimulation, and also capable of estimating LAP or other forms ofcardiac pressure using impedance signals. To provide other atrialchamber pacing stimulation and sensing, pacer/ICD 10 is shown inelectrical communication with a heart 312 by way of a left atrial lead320 having an atrial tip electrode 322 and an atrial ring electrode 323implanted in the atrial appendage. Pacer/ICD 10 is also in electricalcommunication with the heart by way of a right ventricular lead 330having, in this embodiment, a ventricular tip electrode 332, a rightventricular ring electrode 334, a right ventricular (RV) coil electrode336, and a superior vena cava (SVC) coil electrode 338. Typically, theright ventricular lead 330 is transvenously inserted into the heart soas to place the RV coil electrode 336 in the right ventricular apex, andthe SVC coil electrode 338 in the superior vena cava. Accordingly, theright ventricular lead is capable of receiving cardiac signals, anddelivering stimulation in the form of pacing and shock therapy to theright ventricle.

To sense left atrial and ventricular cardiac signals and to provide leftchamber pacing therapy, pacer/ICD 10 is coupled to a CS lead 324designed for placement in the “CS region” via the CS os for positioninga distal electrode adjacent to the left ventricle and/or additionalelectrode(s) adjacent to the left atrium. As used herein, the phrase “CSregion” refers to the venous vasculature of the left ventricle,including any portion of the CS, great cardiac vein, left marginal vein,left posterior ventricular vein, middle cardiac vein, and/or smallcardiac vein or any other cardiac vein accessible by the CS.Accordingly, an exemplary CS lead 324 is designed to receive atrial andventricular cardiac signals and to deliver left ventricular pacingtherapy using at least a left ventricular tip electrode 326 and a LVring electrode 325, left atrial pacing therapy using at least a leftatrial ring electrode 327, and shocking therapy using at least a leftatrial coil electrode 328. With this configuration, biventricular pacingcan be performed. Although only three leads are shown in FIG. 14, itshould also be understood that additional leads (with one or morepacing, sensing and/or shocking electrodes) might be used and/oradditional electrodes might be provided on the leads already shown. Aninterventricular conduction delay 101 already discussed, is also shownin FIG. 14.

A simplified block diagram of internal components of pacer/ICD 10 isshown in FIG. 15. While a particular pacer/ICD is shown, this is forillustration purposes only, and one of skill in the art could readilyduplicate, eliminate or disable the appropriate circuitry in any desiredcombination to provide a device capable of treating the appropriatechamber(s) with cardioversion, defibrillation and pacing stimulation.The housing 340 for pacer/ICD 10, shown schematically in FIG. 15, isoften referred to as the “can”, “case” or “case electrode” and may beprogrammably selected to act as the return electrode for all “unipolar”modes. The housing 340 may further be used as a return electrode aloneor in combination with one or more of the coil electrodes, 328, 336 and338, for shocking purposes. The housing 340 further includes a connector(not shown) having a plurality of terminals, 342, 343, 344, 345, 346,348, 352, 354, 356 and 358 (shown schematically and, for convenience,the names of the electrodes to which they are connected are shown nextto the terminals). As such, to achieve right atrial sensing and pacing,the connector includes at least a right atrial tip terminal (A_(R) TIP)342 adapted for connection to the atrial tip electrode 322 and a rightatrial ring (A_(R) RING) electrode 343 adapted for connection to rightatrial ring electrode 323. To achieve left chamber sensing, pacing andshocking, the connector includes at least a left ventricular tipterminal (V_(L) TIP) 344, a left ventricular ring terminal (V_(L) RING)345, a left atrial ring terminal (A_(L) RING) 346, and a left atrialshocking terminal (A_(L) COIL) 348, which are adapted for connection tothe left ventricular ring electrode 326, the left atrial ring electrode327, and the left atrial coil electrode 328, respectively. To supportright chamber sensing, pacing and shocking, the connector furtherincludes a right ventricular tip terminal (V_(R) TIP) 352, a rightventricular ring terminal (V_(R) RING) 354, a right ventricular shockingterminal (V_(R) COIL) 356, and an SVC shocking terminal (SVC COIL) 358,which are adapted for connection to the right ventricular tip electrode332, right ventricular ring electrode 334, the V_(R) coil electrode 336,and the SVC coil electrode 338, respectively.

At the core of pacer/ICD 10 is a programmable microcontroller 360, whichcontrols the various modes of stimulation therapy. As is well known inthe art, the microcontroller 360 (also referred to herein as a controlunit) typically includes a microprocessor, or equivalent controlcircuitry, designed specifically for controlling the delivery ofstimulation therapy and may further include RAM or ROM memory, logic andtiming circuitry, state machine circuitry, and I/O circuitry. Typically,the microcontroller 360 includes the ability to process or monitor inputsignals (data) as controlled by a program code stored in a designatedblock of memory. The details of the design and operation of themicrocontroller 360 are not critical to the invention. Rather, anysuitable microcontroller 360 may be used that carries out the functionsdescribed herein. The use of microprocessor-based control circuits forperforming timing and data analysis functions are well known in the art.

As shown in FIG. 15, an atrial pulse generator 370 and a ventricularpulse generator 372 generate pacing stimulation pulses for delivery bythe right atrial lead 320, the right ventricular lead 330, and/or the CSlead 324 via an electrode configuration switch 374. It is understoodthat in order to provide stimulation therapy in each of the fourchambers of the heart, the atrial and ventricular pulse generators, 370and 372, may include dedicated, independent pulse generators,multiplexed pulse generators or shared pulse generators. The pulsegenerators, 370 and 372, are controlled by the microcontroller 360 viaappropriate control signals, 376 and 378, respectively, to trigger orinhibit the stimulation pulses.

The microcontroller 360 further includes timing control circuitry (notseparately shown) used to control the timing of such stimulation pulses(e.g., pacing rate, AV delay, atrial interconduction (inter-atrial)delay, or ventricular interconduction (V-V) delay, etc.) as well as tokeep track of the timing of refractory periods, blanking intervals,noise detection windows, evoked response windows, alert intervals,marker channel timing, etc., which is well known in the art. Switch 374includes a plurality of switches for connecting the desired electrodesto the appropriate I/O circuits, thereby providing complete electrodeprogrammability. Accordingly, the switch 374, in response to a controlsignal 380 from the microcontroller 360, determines the polarity of thestimulation pulses (e.g., unipolar, bipolar, combipolar, etc.) byselectively closing the appropriate combination of switches (not shown)as is known in the art.

Atrial sensing circuits 382 and ventricular sensing circuits 384 mayalso be selectively coupled to the right atrial lead 320, CS lead 324,and the right ventricular lead 330, through the switch 374 for detectingthe presence of cardiac activity in each of the four chambers of theheart. Accordingly, the atrial (ATR. SENSE) and ventricular (VTR. SENSE)sensing circuits, 382 and 384, may include dedicated sense amplifiers,multiplexed amplifiers or shared amplifiers. The switch 374 determinesthe “sensing polarity” of the cardiac signal by selectively closing theappropriate switches, as is also known in the art. In this way, theclinician may program the sensing polarity independent of thestimulation polarity. Each sensing circuit, 382 and 384, preferablyemploys one or more low power, precision amplifiers with programmablegain and/or automatic gain control, bandpass filtering, and a thresholddetection circuit, as known in the art, to selectively sense the cardiacsignal of interest. The automatic gain control enables pacer/ICD 10 todeal effectively with the difficult problem of sensing the low amplitudesignal characteristics of atrial or ventricular fibrillation. Theoutputs of the atrial and ventricular sensing circuits, 382 and 384, areconnected to the microcontroller 360 which, in turn, are able to triggeror inhibit the atrial and ventricular pulse generators, 370 and 372,respectively, in a demand fashion in response to the absence or presenceof cardiac activity in the appropriate chambers of the heart.

For arrhythmia detection, pacer/ICD 10 utilizes the atrial andventricular sensing circuits, 382 and 384, to sense cardiac signals todetermine whether a rhythm is physiologic or pathologic. As used herein“sensing” is reserved for the noting of an electrical signal, and“detection” is the processing of these sensed signals and noting thepresence of an arrhythmia. The timing intervals between sensed events(e.g., AS, VS, and depolarization signals associated with fibrillationwhich are sometimes referred to as “F-waves” or “Fib-waves”) are thenclassified by the microcontroller 360 by comparing them to a predefinedrate zone limit (i.e., bradycardia, normal, atrial tachycardia, atrialfibrillation, low rate VT, high rate VT, and fibrillation rate zones)and various other characteristics (e.g., sudden onset, stability,physiologic sensors, and morphology, etc.) in order to determine thetype of remedial therapy that is needed (e.g., bradycardia pacing,antitachycardia pacing, cardioversion shocks or defibrillation shocks).

Cardiac signals are also applied to the inputs of an analog-to-digital(A/D) data acquisition system 390. The data acquisition system 390 isconfigured to acquire intracardiac electrogram signals, convert the rawanalog data into a digital signal, and store the digital signals forlater processing and/or telemetric transmission to an external device402. The data acquisition system 390 is coupled to the right atrial lead320, the CS lead 324, and the right ventricular lead 330 through theswitch 374 to sample cardiac signals across any pair of desiredelectrodes. The microcontroller 360 is further coupled to a memory 394by a suitable data/address bus 396, wherein the programmable operatingparameters used by the microcontroller 360 are stored and modified, asrequired, in order to customize the operation of pacer/ICD 10 to suitthe needs of a particular patient. Such operating parameters define, forexample, the amplitude or magnitude, pulse duration, electrode polarity,for both pacing pulses and impedance detection pulses as well as pacingrate, sensitivity, arrhythmia detection criteria, and the amplitude,waveshape and vector of each shocking pulse to be delivered to thepatient's heart within each respective tier of therapy. Other pacingparameters include base rate, rest rate and circadian base rate.

Advantageously, the operating parameters of the implantable pacer/ICD 10may be non-invasively programmed into the memory 394 through a telemetrycircuit 400 in telemetric communication with the external device 402,such as a programmer, transtelephonic transceiver or a diagnostic systemanalyzer. The telemetry circuit 400 is activated by the microcontrollerby a control signal 406. The telemetry circuit 400 advantageously allowsintracardiac electrograms and status information relating to theoperation of pacer/ICD 10 (as contained in the microcontroller 360 ormemory 394) to be sent to the external device 402 through an establishedcommunication link 404. Pacer/ICD 10 further includes an accelerometeror other physiologic sensor 408, commonly referred to as a“rate-responsive” sensor because it is typically used to adjust pacingstimulation rate according to the exercise state of the patient.However, the physiological sensor 408 may further be used to detectchanges in cardiac output, changes in the physiological condition of theheart, or diurnal changes in activity (e.g., detecting sleep and wakestates) and to detect arousal from sleep. Accordingly, themicrocontroller 360 responds by adjusting the various pacing parameters(such as rate, AV delay, VV delay, etc.) at which the atrial andventricular pulse generators, 370 and 372, generate stimulation pulses.While shown as being included within pacer/ICD 10, it is to beunderstood that the physiologic sensor 408 may also be external topacer/ICD 10, yet still be implanted within or carried by the patient. Acommon type of rate responsive sensor is an activity sensorincorporating an accelerometer or a piezoelectric crystal, which ismounted within the housing 340 of pacer/ICD 10. Other types ofphysiologic sensors are also known, for example, sensors that sense theoxygen content of blood, respiration rate and/or minute ventilation, pHof blood, ventricular gradient, etc.

The pacer/ICD additionally includes a battery 410, which providesoperating power to all of the circuits shown in FIG. 15. The battery 410may vary depending on the capabilities of pacer/ICD 10. If the systemonly provides low voltage therapy, a lithium iodine or lithium copperfluoride cell typically may be utilized. For pacer/ICD 10, which employsshocking therapy, the battery 410 should be capable of operating at lowcurrent drains for long periods, and then be capable of providinghigh-current pulses (for capacitor charging) when the patient requires ashock pulse. The battery 410 should also have a predictable dischargecharacteristic so that elective replacement time can be detected.Accordingly, appropriate batteries are employed.

As further shown in FIG. 15, pacer/ICD 10 is shown as having animpedance measuring circuit 412, which is enabled by the microcontroller360 via a control signal 414. Uses for an impedance measuring circuitinclude, but are not limited to, lead impedance surveillance during theacute and chronic phases for proper lead positioning or dislodgement;detecting operable electrodes and automatically switching to an operablepair if dislodgement occurs; measuring respiration or minuteventilation; measuring thoracic impedance for determining shockthresholds; detecting when the device has been implanted; measuringrespiration; and detecting the opening of heart valves, etc. Theimpedance measuring circuit 412 is advantageously coupled to the switch474 so that any desired electrode may be used. The impedance measuringcircuit 412 also detects the impedance signals discussed above if zLAPis to be estimated, in addition to qLAP. That is, impedance measuringcircuit 412 is an electrical impedance (Z) detector operative to detectan electrical impedance (Z) signal within the patient along at least onesensing vector wherein impedance is affected by cardiac pressure.

In the case where pacer/ICD 10 is intended to operate as an implantablecardioverter/defibrillator (ICD) device, it detects the occurrence of anarrhythmia, and automatically applies an appropriate electrical shocktherapy to the heart aimed at terminating the detected arrhythmia. Tothis end, the microcontroller 360 further controls a shocking circuit416 by way of a control signal 418. The shocking circuit 416 generatesshocking pulses of low (up to 0.5 joules), moderate (0.5-10 joules) orhigh energy (11 to 40 joules), as controlled by the microcontroller 360.Such shocking pulses are applied to the heart of the patient through atleast two shocking electrodes, and as shown in this embodiment, selectedfrom the left atrial coil electrode 328, the RV coil electrode 336,and/or the SVC coil electrode 338. The housing 340 may act as an activeelectrode in combination with the RV electrode 336, or as part of asplit electrical vector using the SVC coil electrode 338 or the leftatrial coil electrode 328 (i.e., using the RV electrode as a commonelectrode). Cardioversion shocks are generally considered to be of lowto moderate energy level (so as to minimize pain felt by the patient),and/or synchronized with an R-wave and/or pertaining to the treatment oftachycardia. Defibrillation shocks are generally of moderate to highenergy level (i.e., corresponding to thresholds in the range of 4-40joules), delivered asynchronously (since R-waves may be toodisorganized), and pertaining exclusively to the treatment offibrillation. Accordingly, the microcontroller 360 is capable ofcontrolling the synchronous or asynchronous delivery of the shockingpulses.

Insofar as LAP estimation is concerned, the microcontroller includes aconduction delay-based LAP estimation system 401 operative to estimateLAP or other forms of cardiac pressure based on parameters derived fromconduction delays using the techniques described above. That is, theestimation system is operative to: measure an electrical conductiondelay in the heart of the patient and estimate cardiac pressure withinthe patient from the electrical conduction delay. In this example,estimation system 401 includes: an LV-RV delay measurement system 403operative to measure interventricular conduction delays within thepatient and an LV-RV-based LAP estimation system 405 operative toestimated LAP from the measured interventricular delays. The estimationsystem also includes, in this example, an LV-RV-based LV EDV estimationsystem 407 operative to estimate LV EDV from the measuredinterventricular delays and an LV-RV-based LV EDP estimation system 409operative to estimate LV EDP from the measured interventricular delays.Estimation system 401 also includes a re-calibration unit or system 411operative to re-calibrate the conversion factors discussed above. AnLAP-based CHF detection system 415 is provide to detect and track CHFbased on LAP. Warning and/or notification signals are generated, whenappropriate, by a therapy/warning controller 417 then relayed to thebedside monitor 18 via telemetry system 400 or to external programmer402 (or other external calibration system.) Controller 417 can alsocontroller an implantable drug pump, if one is provided, to deliverappropriate medications. Controller 417 also controls the adaptiveadjustment of CRT parameters and other pacing parameters, as discussedabove. Terminals for connecting the implanted warning device and theimplanted drug pump to the pacer/ICD are not separately shown.Diagnostic data pertaining to LAP, CHF, therapy adjustments, etc., isstored in memory 394.

Depending upon the implementation, the various components of themicrocontroller may be implemented as separate software modules or themodules may be combined to permit a single module to perform multiplefunctions. In addition, although shown as being components of themicrocontroller, some or all of these components may be implementedseparately from the microcontroller, using application specificintegrated circuits (ASICs) or the like.

Exemplary External Programmer

FIG. 16 illustrates pertinent components of an external programmer 402for use in programming the pacer/ICD of FIG. 15 and for performing theabove-described calibration techniques. For the sake of completeness,other device programming functions are also described herein. Generally,the programmer permits a physician or other user to program theoperation of the implanted device and to retrieve and displayinformation received from the implanted device such as IEGM data anddevice diagnostic data. Additionally, the external programmer can beoptionally equipped to receive and display electrocardiogram (EKG) datafrom separate external EKG leads that may be attached to the patient.Depending upon the specific programming of the external programmer,programmer 402 may also be capable of processing and analyzing datareceived from the implanted device and from the EKG leads to, forexample, render preliminary diagnosis as to medical conditions of thepatient or to the operations of the implanted device.

Now, considering the components of programmer 402, operations of theprogrammer are controlled by a CPU 502, which may be a generallyprogrammable microprocessor or microcontroller or may be a dedicatedprocessing device such as an application specific integrated circuit(ASIC) or the like. Software instructions to be performed by the CPU areaccessed via an internal bus 504 from a read only memory (ROM) 506 andrandom access memory 530. Additional software may be accessed from ahard drive 508, floppy drive 510, and CD ROM drive 512, or othersuitable permanent mass storage device. Depending upon the specificimplementation, a basic input output system (BIOS) is retrieved from theROM by CPU at power up. Based upon instructions provided in the BIOS,the CPU “boots up” the overall system in accordance withwell-established computer processing techniques.

Once operating, the CPU displays a menu of programming options to theuser via an LCD display 514 or other suitable computer display device.To this end, the CPU may, for example, display a menu of specificprogrammable parameters of the implanted device to be programmed or maydisplay a menu of types of diagnostic data to be retrieved anddisplayed. In response thereto, the physician enters various commandsvia either a touch screen 516 overlaid on the LCD display or through astandard keyboard 518 supplemented by additional custom keys 520, suchas an emergency VVI (EVVI) key. The EVVI key sets the implanted deviceto a safe VVI mode with high pacing outputs. This ensures lifesustaining pacing operation in nearly all situations but by no means isit desirable to leave the implantable device in the EVVI mode at alltimes.

Once all pacing leads are mounted and the pacing device is implanted,the various parameters are programmed. Typically, the physicianinitially controls the programmer 402 to retrieve data stored within anyimplanted devices and to also retrieve EKG data from EKG leads, if any,coupled to the patient. To this end, CPU 502 transmits appropriatesignals to a telemetry subsystem 522, which provides components fordirectly interfacing with the implanted devices, and the EKG leads.Telemetry subsystem 522 includes its own separate CPU 524 forcoordinating the operations of the telemetry subsystem. Main CPU 502 ofprogrammer communicates with telemetry subsystem CPU 524 via internalbus 504. Telemetry subsystem additionally includes a telemetry circuit526 connected to telemetry wand 528, which, in turn, receives andtransmits signals electromagnetically from a telemetry unit of theimplanted device. The telemetry wand is placed over the chest of thepatient near the implanted device to permit reliable transmission ofdata between the telemetry wand and the implanted device. Herein, thetelemetry subsystem is shown as also including an EKG circuit 534 forreceiving surface EKG signals from a surface EKG system 532. In otherimplementations, the EKG circuit is not regarded as a portion of thetelemetry subsystem but is regarded as a separate component.

Typically, at the beginning of the programming session, the externalprogramming device controls the implanted devices via appropriatesignals generated by the telemetry wand to output all previouslyrecorded patient and device diagnostic information. Patient diagnosticinformation includes, for example, recorded IEGM data and statisticalpatient data such as the percentage of paced versus sensed heartbeats.Device diagnostic data includes, for example, information representativeof the operation of the implanted device such as lead impedances,battery voltages, battery recommended replacement time (RRT) informationand the like. Data retrieved from the pacer/ICD also includes the datastored within the recalibration database of the pacer/ICD (assuming thepacer/ICD is equipped to store that data.) Data retrieved from theimplanted devices is stored by external programmer 402 either within arandom access memory (RAM) 530, hard drive 508 or within a floppydiskette placed within floppy drive 510. Additionally, or in thealternative, data may be permanently or semi-permanently stored within acompact disk (CD) or other digital media disk, if the overall system isconfigured with a drive for recording data onto digital media disks,such as a write once read many (WORM) drive.

Once all patient and device diagnostic data previously stored within theimplanted devices is transferred to programmer 402, the implanteddevices may be further controlled to transmit additional data in realtime as it is detected by the implanted devices, such as additional IEGMdata, lead impedance data, and the like. Additionally, or in thealternative, telemetry subsystem 522 receives EKG signals from EKG leads532 via an EKG processing circuit 534. As with data retrieved from theimplanted device itself, signals received from the EKG leads are storedwithin one or more of the storage devices of the external programmer.Typically, EKG leads output analog electrical signals representative ofthe EKG. Accordingly, EKG circuit 534 includes analog to digitalconversion circuitry for converting the signals to digital dataappropriate for further processing within the programmer. Depending uponthe implementation, the EKG circuit may be configured to convert theanalog signals into event record data for ease of processing along withthe event record data retrieved from the implanted device. Typically,signals received from the EKG leads are received and processed in realtime.

Thus, the programmer receives data both from the implanted devices andfrom optional external EKG leads. Data retrieved from the implanteddevices includes parameters representative of the current programmingstate of the implanted devices. Under the control of the physician, theexternal programmer displays the current programmable parameters andpermits the physician to reprogram the parameters. To this end, thephysician enters appropriate commands via any of the aforementionedinput devices and, under control of CPU 502, the programming commandsare converted to specific programmable parameters for transmission tothe implanted devices via telemetry wand 528 to thereby reprogram theimplanted devices. Prior to reprogramming specific parameters, thephysician may control the external programmer to display any or all ofthe data retrieved from the implanted devices or from the EKG leads,including displays of EKGs, IEGMs, and statistical patient information,Any or all of the information displayed by programmer may also beprinted using a printer 536.

Additionally, CPU 502 also preferably includes a conduction delay-basedLAP estimation calibration unit 550 operative to perform the calibrationprocedures described above. CPU 502 also preferably includes aconduction delay-based estimated LAP diagnostics controller 551operative to control the display of estimated LAP values and relateddiagnostics. As already noted, physicians are often more familiar withLAP values than conduction delay values and hence benefit from LAP-baseddiagnostics displays that graphically illustrates changes in LAP withinthe patient, such as changes brought on by heart failure.

Programmer/monitor 402 also includes a modem 538 to permit directtransmission of data to other programmers via the public switchedtelephone network (PSTN) or other interconnection line, such as a T1line or fiber optic cable. Depending upon the implementation, the modemmay be connected directly to internal bus 504 may be connected to theinternal bus via either a parallel port 540 or a serial port 542. Otherperipheral devices may be connected to the external programmer viaparallel port 540 or a serial port 542 as well. Although one of each isshown, a plurality of input output (IO) ports might be provided. Aspeaker 544 is included for providing audible tones to the user, such asa warning beep in the event improper input is provided by the physician.Telemetry subsystem 522 additionally includes an analog output circuit545 for controlling the transmission of analog output signals, such asIEGM signals output to an EKG machine or chart recorder.

With the programmer configured as shown, a physician or other useroperating the external programmer is capable of retrieving, processingand displaying a wide range of information received from the implanteddevices and to reprogram the implanted device if needed. Thedescriptions provided herein with respect to FIG. 16 are intended merelyto provide an overview of the operation of programmer and are notintended to describe in detail every feature of the hardware andsoftware of the programmer and is not intended to provide an exhaustivelist of the functions performed by the programmer.

In the foregoing descriptions, LAP or other cardiac pressure values areestimated from conduction delay values. A variety of techniques were setforth for determining or measuring the delay values. In the followingsection, techniques are set forth for estimating delay values fromadmittance or impedance measurements. Note, though, that the estimateddelay values are not necessarily used to then estimate LAP. Rather, theestimated delay values may be used for any suitable purpose. Inparticular, heart failure may be tracked based on the estimated delayvalues. That is, whereas the foregoing set forth techniques inter aliafor tracking heart failure based on LAP values estimated from measuredconduction delays, the following section sets forth techniques fortracking heart failure based on conduction delays estimated frommeasured impedance or admittance values. The two general techniques maybe used in conjunction, where appropriate.

Admittance/Impedance-Based Delay Estimation Techniques

Turning now to FIGS. 17-20, system and methods for estimating conductiondelays from admittance or impedance values and for tracking heartfailure based on the estimated conduction delays will be brieflysummarized. The examples described here principally exploit measuredimpedance values. However, as impedance is the reciprocal of admittance,measured admittance values can alternatively be exploited. Briefly, withreference to FIG. 17, impedance values are measured at block 600 fromwhich conduction delay values are estimated at block 602. The delayvalues are used to detect heart failure events, at block 604, or toperform heart failure trending. A calibration block is also provided forcalibrating the impedance-to-delay estimation procedure. That is, whenthe delays are estimated via block 602, supervising personnel can verifythe estimations are correct by comparing the estimated delays toQuickOpt-based delays obtained in the physician's office. Any differencetherebetween can then be used to adjust or calibrate the impedance todelay estimation procedure. Once properly calibrated, impedancemeasurements (block 608) may be used by the pacer/ICD to estimateconduction delays (block 610), from which heart failure events (or heartfailure trends) 612 are detected.

The estimation of conduction delays based on impedance/admittanceexploits a generally linear correlation between admittance andconduction time delays, which is illustrated in FIG. 18 by way of graph614. In particular, the graph shows the relationship between admittance(1/impedance) and VV delay. This example used the impedance vector fromthe LV ring to the RA ring. The delay was the between the RV and LVwhile the RV was being paced. The relationship in this example shows astrong linear relationship between the VV delay and LVring-RAringadmittance in five patients. Line 616 represents the best-fit linebetween VV delay and admittance given by: VVdelay [ms]=48.712*Admittance[mS]−4.12. Hence, there is also strong correlation between the VV delayand LVring-RAring impedance.

As explained, heart failure can be detected and tracked based onconduction delays. This is illustrated in FIG. 19 by way of graph 618.In this example, developing heart failure caused an increase in thedelay between the RV and the LV measured when the RV is paced. Day 100represents the normalized time when the five patients experienced a HFexacerbation. HF was resolved at day 104 and then patients recovered.The gray shaded area 620 of the graph highlights the time period whenheart failure was occurring. Hence, FIG. 19 shows that the delayincreased during HF and decreased during recovery. The percent change isreferenced to baseline (i.e. zero percent is no HF). The pacer/ICD canbe programmed to set a threshold (for instance 20%) to detect HF events.If the percent change in the delays increase above 20%, an alarm can beused to trigger the patient to take corrective action.

As shown in FIG. 20, one or multiple impedance or admittance vectors 622can be used in either a linear or multi-linear (i.e. quadratic, etc)combination to estimate the conduction delays. The examples of FIG. 20are as follows: 1: LV ring to RV ring; 2. LV ring to RA ring; 3. RV ringto case; 4. LV ring to case; 5. RA ring to case; and 6. RV coil to case.Multiple different equations can be used to determine the delays. In oneexample, where admittance values are detected, the relationship betweenthe admittance and delay is quadratic:

Delay=α*adm²+β*adm+δ

where “adm” refer to admittance and where alpha, beta, and gamma areknown constants developed using a training set of data. Multipleadmittance values can be used to determine a delay:

Delay=α₁*adm₁ ²+β₁*adm₁+α₂*adm₂ ²+β₂*adm₂+δ

where admittance vectors 1 and 2 with their corresponding parameterswere used to determine the delay. In another embodiment, the estimateddelays can be verified each time the patient goes to the physician'soffice such as with the use of delay algorithm or with special softwaresuch as QuickOpt™. When the device is interrogated with the programmer,the programmer would use the QuickOpt procedure to verify the estimateddelays offline (FIG. 17).

Admittance/Impedance-Based Estimation Techniques

Turning now to FIGS. 21-26, techniques will be described for estimatingdelay values from admittance/impedance and for further estimatingcardiac pressure from estimated delay values. FIG. 21 summarizes thetechniques. At step 700, the pacer/ICD detects a value representative ofelectrical immittance within the heart of the patient (such as impedanceor admittance). As noted, admittance is the reciprocal of impedance and,hence, either value can easily be converted to the other. That is, step700 encompasses the detection of either immittance value and theconversion, where appropriate, to the other immittance value.Alternatively, conductance (G) or other suitable electrical parameterscan instead be detected, then used to derive an immittance value.Considering an impedance-based example in more detail, the pacer/ICDdetects electrical impedance (Z) along a sensing vector where impedanceis known to be correlated with electrical conduction delays, which arein turn correlated with cardiac pressure, particularly LAP. For example,the impedance signal may be sensed between an LV tip electrode and an RAtip electrode. As discussed above, there is a strong correlation betweenthe VV delay and LVring-RAring impedance, which permits VV delay to beestimated from LVring-RAring impedance. There is also a strongcorrelation between VV delay and LAP, which permits LAP to be estimatedfrom VV delay. As already shown in FIG. 20, multiple impedance signalsmay be sensed using different sensing vectors passing through differentchambers of the heart so as to permit the pacer/ICD to estimatedifferent conduction delays within different chambers of the heart,assuming appropriate conversion values have been determined andcalibrated. To this end, the implanted system may be equipped, e.g.,with multiple electrodes per lead or with multiple leads per chamber.Unipolar or bipolar sensing systems may be employed.

At step 702, the pacer/ICD estimates an electrical conduction delay inthe heart of the patient from the value representative of immittance,such as by applying a first set of pre-determined conversion factorsderived using linear regression to convert the immittance values toestimated delay values. Depending upon the vector or vectors originallyused to measure immittance at step 700, and the particular conversionfactors to be used, any of a variety of electrical conduction delayswithin the heart can be estimated at step 702. Preferably, though, thepacer/ICD operates to estimate one or more relatively standardconduction delay parameters, such as VV delay or AV delay, as cliniciansare familiar with these values. Moreover, a variety of externalsystems/techniques are available for directly measuring or determiningthe VV and AV delay values for use in calibrating the estimationprocedure of step 702.

Specific exemplary combinations of electrodes are listed below (in TableI) for use in estimating particular delay values. In one example, alinear combination of an “RV coil to case” impedance value, an “LV ringto RA ring” impedance value and an “LV ring to case” impedance value areused to estimate the LV Pacing VV Delay. That is, a predetermined set ofconversion factors are used for converting that particular set ofimpedance values to an estimate of the LV Pacing VV Delay.

QuickOpt or similar systems/techniques can be used to provide analternative determination of the LV Pacing VV delay to calibrate theconversion factors. Neural networks can also be used to estimate delaybased on immittance.

At step 704, in at least some examples, the pacer/ICD then furtherestimates a parameter representative of cardiac pressure within thepatient from the estimated electrical conduction delay, such as byapplying a second set of pre-determined conversion factors derived usinglinear regression to convert the estimated conduction delay to anestimated pressure value. Depending upon the particular delay value orvalues estimated at step 704, and the particular conversion factors tobe used, any of a variety of cardiac pressure values can be estimated atstep 704, such as LAP, LVP, LV EDV or LV EDP. Preferably, though, thepacer/ICD operates to estimate LAP, as clinicians are familiar with LAP.Moreover, a variety of systems/techniques are available for directlymeasuring or determining LAP for use in calibrating the estimationprocedure of step 704.

Insofar as the estimation procedure of step 704 is concerned, thevarious technique techniques described above with reference to FIGS.1-15 can be used. In an example where the VV delay (i.e. LV-RV delay) isinitially estimated from the LVring-RAring impedance, LAP may then beestimated as described above in connection with FIG. 5. As alreadyexplained, the duration of the VV conduction delay depends, in part, onthe sizes of the chambers of the heart. As heart failure progress,pressure within the LV increases and the LV chamber often becomesdistended, resulting in changes in both LVring-RAring immittance and VVconduction delay. Hence, there is, in at least some patients, acorrelation between the VV conduction delay (estimated from immittance)and LV chamber size and LV chamber pressure. Hence, in such patients,there is a correlation between LV-RV delay and LV EDV and LV EDP.Likewise, as heart failure progresses, LAP increases. Accordingly,within at least some patients, there is also a correlation between VVdelay (estimated from immittance) and LAP. The techniques of theinvention exploit this correlation to, e.g., estimate LAP from the VVdelay (estimated from immittance). As already noted, LV EDV and LV EDPmay also be estimated from the LV-RV delay, and hence LV EDV and LV EDPmay also be estimated from LV-RV delays estimated from LVring-RAringimpedance or admittance, within at least some patients.

Neural networks can alternatively be used to estimate delay based onimmittance. Calibration of the conduction delay-to-cardiac pressureestimation procedure of step 704 may be performed generally inaccordance with the techniques described above in connection with FIGS.8-13.

At step 706, the pacer/ICD then adaptively adjusts pacing timingparameters in a closed loop to improve LAP or other cardiac pressurevalues or to modify conduction delays. Techniques described above withreference to FIG. 7 can be used. At step 708, the pacer/ICD then tracksCHF, controls other forms of therapy, generates warnings and/or storesdiagnostic information based on estimated LAP or other cardiac pressurevalues or based on the estimated conduction delays. Techniques describedabove with reference to FIG. 3 can be used.

Note that the functions of steps 706 and 708 may be performed based oneither the conduction delays estimated at step 702 or on the cardiacpressure values estimated at step 704, or some combination thereof. Forexample, estimated conduction delays may be used to adjust pacing timingparameters at step 706. As another example, estimated conduction delaysmay be used to track CHF at step 708.

Impedance-Based LAP Estimation Example

Turning now to FIG. 22, an example is illustrated where averageimpedance (Z) is used to estimate LAP by first estimating the VV (i.e.LV RV) conduction delay. At step 800, the pacer/ICD measures a rawimpedance signal (Z₀) along one or more sensing vectors, such as thoselisted below in TABLE I. In general, impedance signals can be obtainedby transmitting a current between a pair of electrodes and subsequentlymeasuring the voltage between the same or another pair of electrodes.The impedance is calculated as the ratio of the measured voltage to thetransmitted current. Preferably, a tri-phasic impedance pulse waveformis employed to sense the impedance signal. The tri-phasic waveform is afrequency-rich, low energy waveform that provides a net-zero charge anda net-zero voltage. An exemplary tri-phasic pulse waveform is describedin detail in some of the patent applications, cited above, particularlyU.S. patent application Ser. No. 11/558,194, by Panescu et al., entitled“Closed-Loop Adaptive Adjustment of Pacing Therapy based on CardiogenicImpedance Signals Detected by an Implantable Medical Device.” Forconvenience, a portion of that description will now be provided herein.

The tri-phasic waveform possesses many special waveform features andelectrical characteristics that are well suited for probing andmeasuring many types of physiological parameters in the body usingcurrent modulated or voltage modulated pulses. The waveform has negativephases (pulse segments below baseline) that balance positive phases(pulse segments above baseline). Other versions of the waveform may havemore than three phases, may be synchronous or asynchronous, may berectangular or sinusoidal, etc. One version of the waveform uses thesinc(x) sampling waveform. Typically, the tri-phasic waveform is appliedas a current waveform with the resulting voltage being sensed.Alternatively, the waveform is applied as a voltage waveform and sensedas electrical current. In the following descriptions, a current waveformis assumed, unless otherwise noted.

Advantageous properties of the waveform include superior penetration ofsome tissues than conventionally injected signals; better differentialpenetration of tissues than conventionally injected signals for improveddifferentiation and characterization of tissues; broader frequencyspectrum content than conventionally injected signals in order tocharacterize tissue; greater neutrality in the body than conventionallyinjected signals, i.e., the exemplary waveforms do not change theparameter they are trying to measure, and moreover, do not create ionicimbalances or imbalances of charge, voltage, etc., in the tissues or attissue-electrode interfaces. The waveform preferably has a totalduration less than the charging time constant of theelectrode-electrolyte interfaces used to inject and sense the signals.These time constants are typically in the range of a few milliseconds.In one implementation, the duration of the waveform is less than onemillisecond. This waveform feature is helpful for minimizingpolarization effects at these electrode-electrolyte interfaces. Otherfeatures of the waveform include symmetric or asymmetric phase duration,decreasing phase amplitudes, and alternating phase signs. The waveformpreferably has null durations in between phases to provide time to allowcomplete processing of information caused by one phase before the nextphase of the waveform begins. Implementations of the waveform that havenear perfect square wave pulses (or rectangular wave pulses) contain agreat deal of high-frequency content. Near-sinusoidal implementations ofthe waveform may contain less high frequency content than therectangular wave versions.

The features of exemplary waveforms just enumerated provide numerousadvantages, including: eliminating the need for fast digital sampling,minimizing artifacts introduced in the measurement process, increasedtolerance of small phase delays between injected and sensed signals. Thewaveform also lends itself to CMOS realization using low-value switchedcapacitor solutions. Further, the wide frequency spectrum of theinjected signal can be used to implement algorithms that differentiatetissues based on their frequency response, and/or phase delay. The verylow duty-cycle of the waveform makes them safer for patients. Thereduced duty-cycle brings the injected charge and the root-mean-squarevalue of the injected signal well below levels that could be perceivedby the patient or that could induce adverse events.

It is important to note that the net-zero voltage feature, also referredto as the voltage-balanced feature, refers to the voltage formed onblocking capacitors that appear in series with the load. The flow ofcurrent through these capacitors builds up voltage across them. Sincethese capacitors also appear in circuits that are responsible forsensing cardiac activity, it is important that the net voltage built upon them be zero. As a result of the net-zero voltage feature, theinfluence of the waveform on the circuits that sense cardiac activity isminimal. Other features of the waveform derive from the above-mentionednull segments—intra-waveform segments containing no signal—that serveseveral purposes. First, the null segments allow the electronics inprocessing circuits to settle during measurement of phases and second,they allow multiple instances of the waveform to exist in the patient'stissue simultaneously, being staggered by time multiplexing such that aphase of one waveform can be measured during the time that there is nosignal between phases of another waveform.

The waveform provides an elegant and reliable vehicle for measuringbodily impedances in a manner that gives reliably reproducible results.Instead of a conventional technique of trying to sense an instantaneous“snapshot” measurement of a conventionally injected signal, thecircuitry of the pacer/ICD derives an impedance measurement by dividingthe area under the sensed voltage curve by the area of the injectedcurrent waveform. The pacer/ICD can perform this exemplary method by“integrating the curve” of an absolute value of the waveforms. Sometimesthe exemplary implantable device can closely approximate thisintegration without having to perform an integration operation bydirectly measuring and summing the area “under” the curve (e.g., underthe rectangular wave) of the sensed voltage waveform, that is, the areacomposed of the absolute value of the three areas of the three phases ofan exemplary tri-phasic current waveform.

Likewise, the pacer/ICD can integrate, or closely approximate theintegration, by measuring and summing the area “under” the curve (e.g.,the rectangular wave) of the sensed voltage waveform, that is, the areacomposed of the absolute value of the three areas of the three phases.In one implementation, the area of the sensed voltage waveform ismeasured at the output of an integrator circuit. The area of theinjected current waveform is computed by, or preset by, themicro-controller driving the implantable device. The pacer/ICD may thususe this area-based (“areal”) approach to deriving a network ofimpedance measurements over a multi-vector network.

Although the tri-phasic pulse is preferred, other impedance detectionpulses or techniques can be used. Depending upon the particular sensingvector, it may be appropriate to filter the resulting impedance signalto eliminate or reduce any non-cardiogenic components such as anycomponents arising due to respiration or changes in body position ofposture. Bandpass filtering is typically sufficient to filter outrespiratory components.

At step 802, the pacer/ICD then determines an average impedance value(Z) from the raw impedance signal (Z₀) over a period of, e.g. sixteenseconds, which is typically equivalent to about four respiratory cycles.Preferably, an impedance detection circuit is provided within thepacer/ICD that is equipped to determine the average value (Z) of the rawimpedance signal, or the average of various parameters derived from theraw impedance signal such as average peak-to-peak impedance or averagesystolic slope. Systolic slope represents the slope of the cardiogeniccomponent of the impedance signal, i.e. that portion of the signalrepresentative of the beating of the heart of the patient. In oneexample, the maximum of the systolic slope may be exploited, i.e. themaximum of dZ/dt may be calculated for each “cardiogenic” beat withinthe impedance signal, with the max dZ/dt values then averaged over someinterval of time, such as sixteen seconds. In any case, by averaging theraw impedance signal (or parameters derived therefrom) over severalrespiratory cycles, variations due to respiration and the beating of theheart are substantially filtered out. Particular techniques fordetecting or determining the various components of the initial rawimpedance signal are discussed in the above-cited applications,including techniques for identifying or extracting the cardiogeniccomponent.

At step 804, the pacer/ICD inputs predetermined conversion factors frommemory for converting the cardiogenic electrical impedance values toLV-RV conduction delay estimates (or other conduction delay estimates).The conversion factors may be, e.g., the aforementioned α, β and δconversion factors originally discussed above in connection with FIG.17, obtained during a calibration procedure employing linear regression.At step 806, the pacer/ICD then estimates LV-RV (i.e. VV) conductiondelays by calculating:

D _(LV-RV) =α*Z ² +β*Z+δ□

for a single vector where α, β and δ are pre-determined conversionfactors input at step 802 and wherein Z represents the average impedancealong a single vector passing through the LV and RV such as from LVringto RAring.

In an example where two sensing vectors are instead employed, theconduction delays are estimated by calculating:

D _(LV-RV)=α₁ Z ₁ ²+β₁ *Z ₁+α₂ *Z ₂ ²+β₂ *Z ₂+δ

where α₁, β₁, α₂, β₂ and δ are the conversion factors and wherein Z₁represents the average impedance along a first vector passing throughthe LV and RV such as from LVring to RAring and Z₂ represents theaverage impedance along a second, different vector passing through theLV and RV such as from RVring to LAring. In some implementations, threeor more sensing vectors are instead used.

In one particular example, three impedance values are derived fromvarious combinations of electrodes for use in estimating particular AVand VV delays as follows:

TABLE I AV-VV Delay Models Delay Impedance 1 Impedance 2 Impedance 3 LVPacing VV Delay RV coil to case LV ring to RA LV ring to ring case RVPacing VV Delay RV coil to case LV ring to case RA ring to case NoPacing VV Delay LV ring to RA RV ring to LV LV ring to ring ring case RAPacing A-RV Delay RV Coil to case LV ring to RA LV ring to ring case RAPacing A-LV Delay RV coil to case LV ring to RA LV ring to ring case RAPacing VV Delay LV ring to RA RV ring to LV RA ring to ring ring case NoPacing A-RV Delay LV ring to RA LV ring to case RA ring to ring case NoPacing A-LV Delay RV coil to case RA ring to case RV ring to case

A linear combination of the three impedances may be used to calculatethe corresponding delay value. For example, a linear combination of the“RV coil to case” impedance value, the “LV ring to RA ring” impedancevalue and the “LV ring to case” impedance value may be used to estimatethe LV Pacing VV Delay, using predetermined conversion factorsappropriate for estimating that particular delay value from thoseparticular impedance values.

At step 808, the pacer/ICD then inputs conversion factors for convertingconduction delay values to LAP values within the patient. The conversionfactors may be, e.g., predetermined slope and baseline values obtainedduring a calibration procedure employing linear regression. Generaltechniques for determining and updating slope and baseline values arediscussed above in connection with FIGS. 8-13. Note, though, that thespecific slope and baseline values may differ when using the techniqueof FIG. 22 as compared to the techniques of FIGS. 1-15 because the slopeand baseline values for use with FIG. 22 must be appropriate for usewith estimated delay values rather than measured delay values. Moreover,different conversion factors are typically required at step 808depending upon the particular vector used to derive the impedance signalfrom which the conduction delay is estimated.

At step 810, the pacer/ICD estimates LAP within the patient from theestimated conduction delays by calculating:

LAP=D _(LV-RV)*SLOPE+BASELINE.

As indicated by step 812, the pacer/ICD repeats the estimation procedurefor each heartbeat to track LAP(t). At step 814, the pacer/ICD adjustsits timing delays (such as the VV and AV delays) in an effort reduce LAPso as to mitigate CHF or other heart ailments. Adjustment techniquesalready described above in connection with FIGS. 5 and 7 may be used.

Admittance-Based LAP Estimation Example

FIG. 23 provides an example where average admittance (Y) is insteadexploited. The steps of FIG. 23 are similar to those of FIG. 22 and willbe discussed only briefly. At step 900, the pacer/ICD measures a rawadmittance signal (Y₀) and, at step, 902, determines an averageadmittance value (Y) from the raw admittance signal (Y₀) over a periodof, e.g. sixteen seconds. In some examples, various parameters derivedfrom the raw admittance signal may instead be exploited, such as averagepeak-to-peak admittance. At step 904, the pacer/ICD inputs predeterminedconversion factors from memory for converting the average admittancevalues to LV-RV conduction delay estimates (or other conduction delayestimates). The conversion factors may be, e.g., similar to theaforementioned □□, □ and □□ conversion factors discussed above inconnection with FIG. 22, but appropriate for use with admittance ratherthan impedance.

At step 906, the pacer/ICD then estimates LV-RV (i.e. VV) conductiondelays by calculating:

D _(LV-RV) =α*Y ² +β*Y+δ

for a single vector where α, β and δ are the conversion factorsappropriate for use with admittance and wherein Y represents the averageadmittance along a single vector passing through the LV and RV, such asfrom LVring to RAring.

In an example where two sensing vectors are instead employed, theconduction delays are estimated by calculating:

D _(LV-RV)=α₁ *Y ₁ ²+β₁ *Y ₁+α₂ *Y ₂ ²+β₂ *Y ₂+δ

where α₁, β₁, α₂, β₂ and δ are the appropriate conversion factors andwherein Y₁ represents the average admittance along a first vectorpassing through the LV and RV such as from LVring to RAring and Y₂represents the average admittance along a second, different vectorpassing through the LV and RV such as from RVring to LAring.

At step 908, the pacer/ICD then inputs conversion factors for convertingconduction delay values to LAP values within the patient. The conversionfactors may again be, e.g., predetermined slope and baseline valuesobtained during a calibration procedure employing linear regression. Atstep 910, the pacer/ICD estimates LAP within the patient from theestimated conduction delays by again calculating:

LAP=D _(LV-RV)*SLOPE+BASELINE.

Also, as indicated by step 912, the pacer/ICD can repeat the estimationprocedure for each heartbeat to track LAP(t) and, at step 914, thepacer/ICD can adjust its timing delays in an effort reduce LAP.

Hence, FIGS. 22-23 illustrate exemplary techniques for estimated LAPbased on conduction delay values estimated from impedance/admittancevalues. These techniques may be used in addition to, or as analternative to, the LAP estimation techniques of FIGS. 1-15, which areinstead based on measured conduction delays values. In someimplementations, the pacer/ICD is equipped to perform both estimationtechniques and so the memory of the pacer/ICD stores the variousconversion factors and retrieves the appropriate factors depending uponthe particular estimation technique currently being used, as specifiedby the programming of the device. LAP values estimated using differenttechniques may be averaged together.

Admittance/Impedance-Based Delay Estimation Calibration

FIG. 24 illustrates an exemplary technique for calibrating theimmittance-to-delay estimation procedures of FIGS. 22-23. At step 1000,the pacer/ICD estimates conduction delays (such as LV-RV delays) frommeasured immittance values within the patient using various conversionfactors (FIGS. 22-23). At step 1002, an external system, such as adevice programmer, measures the same conduction delays for use incalibration. For example, if the external device is equipped with theQuickOpt system, data generated by QuickOpt can be used to specify theLV-RV conduction delay within the patient for comparison against anLV-RV delay estimated by the pacer/ICD. For the sake of completeness,pertinent portions of the QuickOpt code have been provided in theattached appendix (Appendix A). The example of Appendix A primarilyoperates to set RV thresholds. However, the LV-RV delay may be obtainedusing information generated by the code. That is, in the code. “ndx_lv”is the location of the LV QRS. “ndx_rv” is the location of the RV QRS.Hence, the LV-RV delay may be obtained by subtracting ndx_rv from ndx_lv(or vice versa).

At step 1004, the external system verifies the correct estimation madeby the pacer/ICD by comparing the estimated values from step 1000 to themeasured values from step 1002. At step 1006, the external systemadjusts the conversion factors (if needed) of the pacer/ICD to improvepacer/ICD-based LAP/delay estimations. In this regard, the externalsystem may transmit programming commands to the pacer/ICD to reprogramit with adjusted conversion factors. By improving or calibrating theconversion factors, the pacer/ICD can more accurately estimateconduction delays, which in turn allows the device to more accuratelyestimate LAP. As already explained in connection with FIG. 16, theexternal programmer can also be equipped with systems for re-calibratingthe conduction delay-to-LAP estimation procedures employed by thepacer/ICD. Preferably, both stages of the overall LAP estimationprocedure employed by the pacer/ICD are periodically recalibrated.

Note also that if the pacer/ICD itself is equipped to reliably measureconduction delays, then those measured delays can additionally oralternatively be used to periodically recalibrate theimmittance-to-delay estimation procedure (or vice versa). Also, at leastsome pacer/ICDs are equipped with a device-based QuickOpt system toallow conduction delays to be readily obtained within the device. Theseconduction delay values can also be used calibrate theimmittance-to-delay estimation procedure. See, for example, U.S. patentapplication Ser. No. ______, to Min et al., entitled “Systems andMethods for Controlling Ventricular Pacing in Patients with LongIntra-Atrial Conduction Delays.” (A07e1025) See, also, U.S. Pat. No.7,248,925, to Bruhns et al., entitled “System and Method for DeterminingOptimal Atrioventricular Delay based on Intrinsic Conduction Delays.”

For the sake of completeness, devices equipped to implement thetechniques of FIGS. 21-24 will now be briefly described.

Exemplary Pacer/ICD and External Programmer

A simplified block diagram of internal components of a pacer/ICD 10′ isprovided in FIG. 25, wherein the pacer/ICD includes components forestimating LAP based on delays values estimated from immittance. Most ofthe components are the same as in pacer/ICD 10 of FIG. 15 and onlypertinent differences will be noted. The pacer/ICD 10 includes animpedance/admittance measuring circuit 412′ for measuring or detectingan immittance value. Insofar as immittance-based delay estimation isconcerned, the microcontroller 360′ includes an immittance-basedconduction delay-based estimation system 1101 operative to estimateconduction delays based on immittance values using the techniquesdescribed above in FIGS. 21-24. Estimation system 1101 includes anaverage impedance measurement system 1103 and additionally, oralternatively, includes an average admittance measurement system 1105.Estimation system 1101 also includes animpedance/admittance-to-conduction delay conversion unit 1107 operativeto convert impedance/admittance values to conduction delays using, e.g.,conversion factors, as already described. An on-board re-calibrationsystem 1109 may be provided for calibrating the conversion factors usedto convert impedance/admittance to conduction delays, if the device isequipped to reliably measure (or otherwise obtain) conduction delays.

The microcontroller also includes, as in the embodiment of FIG. 15, aconduction delay-based LAP estimation system 401 operative to estimatecardiac pressure from electrical conduction delays (in this caseestimated delays rather than measured delays.) Although not shown, anLAP-based CHF detection system (such as system 415 of FIG. 15) may alsobe provided to detect and track CHF based on LAP. Warning and/ornotification signals are generated, when appropriate, by atherapy/warning controller 417 then relayed to the bedside monitor 18via telemetry system 400 or to external programmer 402 (or otherexternal calibration system.) Controller 417 can also control animplantable drug pump, if one is provided, to deliver appropriatemedications. Controller 417 also controls the adaptive adjustment of CRTparameters and other pacing parameters, as discussed above. Terminalsfor connecting the implanted warning device and the implanted drug pumpto the pacer/ICD are not separately shown. Diagnostic data pertaining toestimated conduction delays, LAP, CHF, therapy adjustments, etc., isstored in memory 394.

Depending upon the implementation, the various components of themicrocontroller may be implemented as separate software modules or themodules may be combined to permit a single module to perform multiplefunctions. In addition, although shown as being components of themicrocontroller, some or all of these components may be implementedseparately from the microcontroller, using application specificintegrated circuits (ASICs) or the like.

FIG. 26 illustrates pertinent components of an external programmer 402′for use in programming the pacer/ICD of FIG. 26 and for performing theabove-described calibration techniques. Most of the components are thesame as in programmer 402 of FIG. 16 and only pertinent differences willbe noted. CPU 502′ includes, in this example, an immittance-based delayestimation calibration unit 1250 operative to perform the calibrationprocedures described above for calibrating the immittance-to-delayconversion performed by the pacer/ICD of FIG. 25. CPU 502′ alsopreferably includes an immittance delay-based estimated delaydiagnostics controller 1251 operative to control the display ofestimated delay values and related diagnostics. Although not shown inFIG. 26, the programmer device may also include the LAP estimationcalibration and diagnostics components of the programmer of FIG. 16.

Using Intra-Cardiac Conduction Time Delays to Predict/Trend HeartFailure

Still further, the pacer/ICD may be equipped to predict heart failureevents and to trend heart failure progression. In this regard, duringHF, the myocardium of the heart remodels such that the cardiac outputdecreases. During the remodeling, intracardiac conduction time delayshave been shown to change. By monitoring the changes in conductiondelays, the pacer/ICD can monitor HF progression and detect theoccurrence of HF events.

More specifically, patients with heart failure may be candidates for aCRT device. A heart failure patient with an implantable CRT device hasat least three pacing leads implanted therein (RA, RV, and LV). Each ofthese leads may be used to stimulate the heart to contract eitherindependently or synchronously. When a single chamber is stimulated,cardiac contraction occurs in the stimulated chamber, which is usuallyfollowed by a subsequent cardiac contraction in other chambers after thestimulus has had sufficient time to reach the other chamber. The timedelay between contractions of any two chambers is dependent on variousfactors, such as conduction velocity and the distance to be traveled. Itis believed that the time delay between the contraction of any twocardiac chambers following either a natural occurring stimulus or anexternally administered stimulus is indicative of the degree of cardiacfailure and is also proportional to the cardiac chamber size (asexplained above), such that longer delays may be associated with aworsening cardiac status. Hence, one or a combination of conductiondelays can be used to predict HF events and trend HF progression.

The inter-ventricular conduction time delay following the delivery of aleft ventricular pacing stimulus may be used to estimate the size and/orLV filling pressure. At the time a pacing stimulus is delivered to theLV, the chamber is filled with blood and corresponds to LV EDV. Thepacing stimulus causes the LV muscle to depolarize and subsequentlycontract. While the LV depolarization occurs, the depolarization wavefront travels across the LV toward the right ventricle and ultimatelycauses the RV to depolarize and subsequently contract. The delay betweenthe time when the LV pacing stimulus was administered and the time whenthe RV depolarizes may be proportional in at least some patients to theLV EDV. For HF, the LV EDV increases as HF progresses, thus the LV to RVconduction time delay will increase as HF worsens, in at least somepatients. The pacing stimulus could also be applied to the RVventricular while measuring the time delay until the LV depolarizes.Other delays that might be used are the paced atrium to recordedventricles (both RV and LV), intrinsic activity either between theatrium and the ventricles or between the right and left ventricles.

The conduction time delay can be used in a variety of ways to trend HFprogression and to detect HF events. In one embodiment, to trend HFprogression is to measure the change in time delay from baseline. Thebaseline is set to when the patient does not experience any HF events.If the change in time delay increases. HF is thus getting worse. Adecrease in time delay in indicative of an improvement in HF. The changein time delay can be represented in time (i.e. milliseconds) or as apercent change from baseline:

${PercentChange} = {\frac{{CurrentMeasurement} - {Baseline}}{Baseline}*100\%}$

By using the change in time delays (either as a percent or inmilliseconds), the pacer/ICD can set a threshold to detect HF events.For example, if the time delay increases more than 20% over baseline, analarm would be triggered to notify the patient to change medication orseek medical attention.

In another embodiment, the threshold to detect HF events is insteadbased on the previous values of the delays. If the patient were slowlyworsening, the threshold for an HF event would be slowly increasing.This method allows the natural progression of HF to occur withouttriggering false alarms. However, if a sudden change were detected intime delays, such as a HF exacerbation, the time delay would increaseabove the threshold and trigger the alarm.

Another trending algorithm is:

$r = {1 - \frac{{Delay}_{LongTerm}}{{Delay}_{ShortTerm}}}$HF_Index = sum(max (r, 0))

where the long-term delay is a 10 to 50 day moving average of thedelays, and the short-term delay is a 1 to 9 day moving average of thedelays. During a HF event, the short-term delay is larger than thelong-term delay, causing r to be positive. Since HF_Index is acumulative sum, a positive value of r causes the HF_Index to increase.An HF event causes the HF_Index rise, and if stays above a threshold fora certain number of days, an alarm is triggered. If r is not positivefor a certain number of days (for instance, 3 days), HF_index is resetto zero.

Other cumulative sum algorithms that incorporate comparing long-termdelays (10 to 50 days) to short-term delays (1-9 days) may also be used.Any combination of delays might also be used in these detectionalgorithms (for instance, RV pacing RV-LV delay and Intrinsic RA-RVdelay). To determine the delays, the pacer/ICD can use a variety ofmethods. One such method uses a built-in delay algorithm. In oneexample, the set of measured delays is:

Paced LV RV to LV Delay

Paced RV RV to LV Delay

Paced RA RA to RV Delay

Paced RA RA to LV Delay

Paced RA RV to LV Delay

No Pacing RA to RV Delay

No Pacing RA to LV Delay

No Pacing RV to LV Delay

Any one delay or any combination of the delays can be used by thepacer/ICD for HF trending/predicting. The techniques described above canbe used to estimate these or other delays for HF trending/predicting, aswell as for use in estimating LAP, as already described.

Hence, a pacer/ICD or external system can be equipped: to use theintracardiac conduction time delays to trend HF progression and todetect HF events; to use a cumulative sum algorithm to trend HF and todetect HF events; to use a threshold algorithm to trend HF and to detectHF event; to use QuickOpt (or similar) to determine the conductiondelays; to use different impedance vectors to determine conductiondelays; and/or to use QuickOpt to verify an estimate conduction delays

In general, while the invention has been described with reference toparticular embodiments, modifications can be made thereto withoutdeparting from the scope of the invention. Note also that the term“including” as used herein is intended to be inclusive, i.e. “includingbut not limited to.”

APPENDIX A %Setting threshold for find RV max_rv=max(rv);mn_rv=mean(rv); thshld_rv=0.55*(max_rv-mn_rv)+mn_rv; %threshold I findwhere the RV crosses the threshold %Finding when RV crosses thresholdndx=find(rv>thshld_rv); dndx=diff([0; ndx]); sndx=find(dndx>10);strt_ndx=ndx(sndx); dndx=diff([ndx; length(rv)]); endx=find(dndx>10);end_ndx=ndx(endx); I find the maximum signal when the V channel crossesthe threshold, and call that my ndx %Finding maximum for index of RVndx_rv=zeros(length(strt_ndx),1); for i=1:length(strt_ndx) [jnk,mx_ndx]=max(rv(strt_ndx(i):end_ndx(i))); ndx_rv(i)=strt_ndx(i)+mx_ndx-1; end Make sure that each V eventcaptures based on size of signal %Making sure caption occurred bad_ndx=[]; if ndx_lv(end)+25>length(lv)  ndx_lv(end)=[ ]; end fori=1:length(ndx_lv)  mx_lv=max(lv(ndx_lv(i):ndx_lv(i)+12));  if mx_lv<69  bad_ndx=[bad_ndx i];  end end ndx_lv(bad_ndx)=[ ]; This next sectionaligns the LV with the RV to match sure they are matched with eachother%Making sure LV and RV are same length if ~isempty(ndx_lv) &&~isempty(ndx_rv)  if length(ndx_rv)~=length(ndx_lv)   whilendx_rv(1)<ndx_lv(1)    ndx_rv(1)=[ ];   end   whilendx_lv(end)>ndx_rv(end)    ndx_lv(end)=[ ];   end  end end iflength(ndx_rv)~=1ength(ndx_lv)  %disp(′error: RV ~= LV: LV′)  %RemovingT waves from RV ndx  diff_rv=diff(ndx_rv);  diff_ndx=find(diff_rv<100); ddndx=diff([0;diff_ndx]);  diff_ndx=diff_ndx(ddndx~=1); ndx_rv(diff_ndx+1)=[ ];  %Aligning RV with LV indices  iflength(ndx_rv)<length(ndx_lv)   tmp_ndx=zeros(length(ndx_rv),1);  bad_ndx=[ ];   for i=1:length(ndx_rv)    tmp=find(ndx_lv>ndx_rv(i)-56& ndx_lv<ndx_rv(i)+90);    if ~isempty(tmp)     if length(tmp)>1     tmp2=ndx_lv(tmp)-ndx_rv(i);      [jnk,tmp3],=min(abs(tmp2));     tmp=tmp(tmp3);     end     tmp_ndx(i),=ndx_lv(tmp);    else    bad_ndx=[bad_ndx i];    end   end   ndx_rv(bad_ndx)=[ ];  ndx_lv=tmp_ndx;   ndx_lv(ndx_lv==0)=[ ];  elseiflength(ndx_rv)>length(ndx_lv)   tmp_ndx=zeros(length(ndx_lv),1);  bad_ndx=[ ];   for i=1:length(ndx_lv)    tmp=find(ndx_rv>ndx_lv(i)-80& ndx_rv<ndx_lv(i)+80);    if ~isempty(tmp)     if length(tmp)>1     tmp2=ndx_rv(tmp)-ndx_lv(i);      [jnk,tmp3]=min(abs(tmp2));     tmp=tmp(tmp3);     end     tmp_ndx(i)=ndx_rv(tmp);    else    bad_ndx=[bad_ndx i];    end   end   ndx_lv(bad_ndx)=[ ];  ndx_rv=tmp_ndx;   ndx_rv(ndx_rv==0)=[ ];  end end

What is claimed is:
 1. A system for estimating cardiac pressure within apatient using an implantable medical device, the system comprising: animmittance detection system operative to detect a value representativeof electrical immittance within the heart of the patient; and animmittance-based electrical conduction delay estimation unit operativeto estimate an electrical conduction delay in the heart of the patientfrom the value representative of immittance.
 2. The system of claim 1further including a conduction delay-based cardiac pressure estimationunit operative to estimate cardiac pressure within the patient from theestimated electrical conduction delay.